101 results on '"S. Gilfillan"'
Search Results
2. A Comparison of Psychotic and Nonpsychotic Substance Users in the Psychiatric Emergency Room
- Author
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J. Battaglia, Thomas J. Carmody, A. J. Rush, P. Orsulak, J. B. Sweeney, S. Gilfillan, and Cynthia A. Claassen
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Substance-Related Disorders ,Adjustment disorders ,Comorbidity ,Adjustment Disorders ,Patient Admission ,medicine ,Humans ,Psychiatry ,Emergency Services, Psychiatric ,Illicit Drugs ,business.industry ,Alcohol users ,Middle Aged ,medicine.disease ,Texas ,Substance Abuse Detection ,Substance abuse ,Alcoholism ,Psychiatry and Mental health ,Psychotic Disorders ,Clinical diagnosis ,Marital status ,Female ,Substance use ,Level of care ,Seclusion ,business ,Clinical psychology - Abstract
Current illicit drug and alcohol users were identified by laboratory evaluation of urine samples from nonpsychotic patients without a primary clinical diagnosis of a substance use disorder seen in a psychiatric emergency room. Urine screens revealed that 32 of 93 nonpsychotic patients (34 percent) had used a substance just before visiting the emergency room. Compared with nonusers, users were more often Caucasian females with adjustment disorders who admitted their previous substance use. The prevalence of concurrent use among nonpsychotic patients was higher than among psychotic patients. Nonpsychotic and psychotic users differed in gender, marital status, level of suicidality, self-report of use, the clinician's suspicion of use, use of seclusion during the visit, admitting status, level of care, and disposition.
- Published
- 1998
3. Characterization of mussel beds with residual oil and the risk to foraging wildlife 4 years after theExxon valdezoil spill
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Paul D. Boehm, Rolf Hartung, Paul J. Mankiewicz, Edward S. Gilfillan, Keith R. Parker, David S. Page, Jerry M. Neff, and James E. O. Reilly
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animal structures ,biology ,Ecology ,Health, Toxicology and Mutagenesis ,fungi ,Residual oil ,Mussel ,Bivalvia ,biology.organism_classification ,Otter ,Mytilus ,Fishery ,chemistry.chemical_compound ,Dry weight ,chemistry ,biology.animal ,Environmental Chemistry ,Environmental science ,Petroleum ,Mollusca - Abstract
The grounding of the Exxon Valdez on March 24, 1989, released about 41 million L of crude oil into the waters of Prince William Sound, Alaska, USA, and oiled about 16% of the Prince William Sound shoreline to various degrees. Although winter storms, cleanups, and natural biodegradation have removed the majority of the oil on the shorelines, some residual oil still remains trapped in sediments immediately below mussel beds. This oil was protected from wave action by the dense covering of mussels. Field surveys found that mussels in such beds constituted less than 3% of the mussels available for foraging in two areas that had been extensively oiled in 1989. Levels of polycyclic aromatic hydrocarbons (PAHs) in these mussels were also measured. Mean PAH concentrations in mussel tissues ranged between 20 and 4,000 ng/g dry weight and in sediments between 20 and 26,000 ng/g dry weight. Assuming that the species considered most at risk (i.e., harlequin ducks, black oystercatchers, and sea otters) consumed the mussel proportion of their diets exclusively from such beds (at either the median or 95th percentile of mussel tissue PAH concentration), the estimated PAH dosage they would receive was one to three orders of magnitude below doses known to cause sublethal effects in surrogate species. Considering the low frequency of mussel beds with residual oil, the patchy distribution of remaining weathered oil residues, and the relatively low PAH concentrations in the mussels, the risk of quantifiable injury at the level of an individual bird or otter, or at the population level, is minimal. Furthermore, based on a review of the mussel PAH data in Prince William Sound, the risk to wildlife has been minimal since 1990, 1 year after the spill.
- Published
- 1996
4. Use of remote sensing to document changes in marsh vegetation following the Amoco Cadiz oil spill (Brittany, France, 1978)
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Nicole P. Maher, Cecile M. Krejsa, Christopher D. Ball, David S. Page, Jeremy B. Meltzer, Edward S. Gilfillan, and Mary E. Lanphear
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Hydrology ,Pollution ,geography ,Marsh ,geography.geographical_feature_category ,media_common.quotation_subject ,Sediment ,Intertidal zone ,Aquatic Science ,Oceanography ,Remote sensing (archaeology) ,Salt marsh ,Vegetation type ,Plant cover ,Environmental science ,media_common - Abstract
Image analysis of historical aerial photographs was used to examine the effects of the Amoco Cadiz oil spill and resulting clean-up on marsh ecology. Two heavily oiled marsh systems were compared. The marsh which received no clean-up recovered to its prior condition. The marshes in the system cleaned by sediment removal were extensively altered as a result of changes in intertidal height of the sediment surface.
- Published
- 1995
5. Ranking heart surgeons has pitfalls
- Author
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Ian S Gilfillan
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medicine.medical_specialty ,Team sport ,business.industry ,General Engineering ,General Medicine ,medicine.disease ,Cardiac surgery ,Ranking (information retrieval) ,Dilemma ,Cardiothoracic surgery ,General Earth and Planetary Sciences ,Medicine ,Medical emergency ,Letters ,business ,human activities ,General Environmental Science - Abstract
EDITOR–Dyer reports that heart surgeons are to be rated according to success in bypass surgery.1 Cardiac surgery is a team sport, and each player can influence the score. The dilemma I face as a surgeon is that the result is mine, although the poor performance may not always …
- Published
- 2003
6. Atherosclerosis (PP-022)
- Author
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N. I. Grachev, E. V. Markelova, R. Poledne, Kazunori Onoé, H. Tlaskalova, K. Sato, Mitra Zarebavani, Z. Tonar, E. P. Turmova, Y. Guo, X. Li, S. Gilfillan, Nasrin Dashti, J. Bartova, Sachiko Miyake, R. M. Gromovoy, Kazuya Iwabuchi, Nahid Einollahi, E. Bladbjerg, I. V. Chikalovets, X. Zhou, L. Wang, A. A. Silaev, N. Hagiwara, P. Rossman, K. Gomita, G. L. Sorensen, E. A. Bychkov, M. Satoh, A. A. Levitskiy, M. Yoshida, C. Yao, R. Stepankova, U. Holmskov, G. D. Sim, H. Ogura, and R. S. Pankratev
- Subjects
Immunology ,Immunology and Allergy ,General Medicine - Published
- 2010
7. Substance use among patients with a psychotic disorder in a psychiatric emergency room
- Author
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J. Battaglia, S. Gilfillan, Orsulak P, Claassen Ca, A.J. Rush, and Thomas J. Carmody
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Adult ,Male ,medicine.medical_specialty ,Psychosis ,Younger age ,Self Disclosure ,Alcohol Drinking ,Substance-Related Disorders ,Logistic regression ,Sensitivity and Specificity ,Sampling Studies ,Risk Factors ,medicine ,Confidence Intervals ,Odds Ratio ,Humans ,Prospective Studies ,Psychiatry ,Male gender ,Emergency Services, Psychiatric ,Drug screens ,business.industry ,Diagnostic Tests, Routine ,Alcohol users ,Middle Aged ,Laboratory results ,medicine.disease ,Texas ,Hospitalization ,Psychiatry and Mental health ,Cross-Sectional Studies ,Logistic Models ,Psychotic Disorders ,Diagnosis, Dual (Psychiatry) ,Female ,Substance use ,Triage ,business ,Emergency Service, Hospital ,Follow-Up Studies - Abstract
OBJECTIVE This study used laboratory tests to identify current drug and alcohol users among psychotic patients seeking treatment in an urban psychiatric emergency room. Rates of clinician-suspected use and self-reported use were compared, as were treatment and disposition of users and nonusers. METHODS Logistic regression modeling was used to identify factors that differentiated current substance users from nonusers in a sample of 112 psychotic patients. RESULTS Laboratory analyses revealed that 24 of the 112 psychotic patients (21 percent) had used alcohol or an illegal substance before visiting the emergency room. Younger age, male gender, African-American ethnicity, clinician-suspected substance use, and presentation in the emergency room between 7 p.m. and 7 a.m. were associated with a higher likelihood of positive results on the urine test. Only five of the patients who had positive results (21 percent) self-reported substance use. Clinicians suspected that 59 patients (53 percent) were under the influence; however, only 17 of those suspected (29 percent) had positive laboratory results. Patients with positive laboratory results required more intense care in the psychiatric emergency room and were more often hospitalized. CONCLUSIONS Some demographic and clinical factors were associated with concurrent substance use among psychotic patients in the emergency room. Clinicians' suspicions of use in this sample of psychotic patients lacked specificity due to the fact that potential use was suspected in a large number of cases for which laboratory results were negative. In contrast, self-reported use was uncommon among patients with positive results. Because neither clinician judgment nor patient self-report meaningfully predicts current substance use, routine urine drug screens may be appropriate.
- Published
- 1997
8. TIDAL AREA DISPERSANT EXPERIMENT, SEARSPORT MAINE: AN OVERVIEW
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J. C. Foster, Sandy Hebert, Sheldon D. Pratt, R. P. Gerber, Erin Pendergast, D. Vallas, David S. Page, J. R. Hotham, Edward S. Gilfillan, and S. A. Hanson
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geography ,geography.geographical_feature_category ,Community level ,Environmental chemistry ,Oil spill ,Environmental engineering ,Sediment ,Intertidal zone ,Environmental science ,Chemical fate ,Crude oil ,Cove ,Dispersant - Abstract
On August 19, 1981, two test spills of Murban crude oil were carried out in Long Cove, Searsport, Maine. One spill was chemically dispersed; the other was not. Measurements were made to make quantitative comparisons of the chemical fates and biological effects of the two spills. Hydrocarbon analyses were carried out on water samples, animal tissue samples, intertidal sediment samples, and subtidal sediment samples. Biological measurements were carried out at the community level, whole animal level, and biochemical level of organization. No significant biological effects attributable to the dispersed oil spill were observed. This lack of effects is, in part, a result of changes in the physical and chemical properties of dispersed oil which help limit its availability and toxicity. The chemical fate and biological effects of the undispersed oil spill were typical of those reported from actual oil spill sites. Oil was incorporated into sediments and animal tissue. On the community level of organization mortality, reduced diversity and evenness, increased population density, and increased dominance by opportunists were all observed immediately after the spill, and up to 1 year later. On the whole animal level of organization, no effects on scope-for-growth were observed in two filter feeding bivalves. On the biochemical level of organization, activities of two sensitive enzyme systems were elevated.
- Published
- 1985
9. A Clinical Estimation of the Blood Pressure in the Minute Vessels of the Human Skin by the Method of Elevation and Reactive Hyperemia
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Frank H. Leeds, Norman E. Freeman, and Rutherford S. Gilfillan
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Leg ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Blood Pressure ,Blood Pressure Determination ,Hyperemia ,Human skin ,Prognosis ,medicine.disease ,Arterial insufficiency ,Surgery ,Blood pressure ,Amputation ,Physiology (medical) ,Internal medicine ,medicine ,Cardiology ,Humans ,Cardiology and Cardiovascular Medicine ,business ,Reactive hyperemia ,Foot (unit) ,Skin - Abstract
The filling pressure in the minute vessels of the skin of the foot has been estimated by a method of elevation and reactive hyperemia. A series of 90 observations was made on 78 patients. This test has been found helpful in evaluating the degree of arterial insufficiency, permitting a more accurate selection of patients to be treated by conservative methods, local amputation or more radical procedures.
- Published
- 1954
10. THE CHARACTERISTICS OF THORACIC DUCT LYMPH IN MAN
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N. E. Freeman, R. S. Gilfillan, Grace Singer, N. L. Petrakis, K. H. Kelly, Ralph L. Byron, Fauno Cordes, Laurens P. White, and H. R. Bierman
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Male ,medicine.medical_specialty ,business.industry ,Articles ,General Medicine ,Peripheral blood ,Thoracic duct ,Thoracic Duct ,Peripheral ,Lymphatic System ,medicine.anatomical_structure ,Lymphatic system ,Immunology ,medicine ,Humans ,Thoracic duct lymph ,Lymph ,Lymphocytes ,Radiology ,business - Abstract
The thoracic duct is generally accepted as the major pathway of lymphocytes enroute to the circulating blood (1, 2, 3), accounting for approximately 70 per cent of all the lymphocytes in the peripheral blood. The remainder of the lymphocytes are said to enter the blood directly via the lymph from other sites (2). Reliable information concerning the hematologic content of lymph in the thoracic duct of man has been fragmentary and limited to chance observations in few patients (4). The thoracic duct lymph is reported to flow from one to six hours after death (5, 6). Consequently, an attempt was made to study the cellular components of human lymph obtained by cannulation of the thoracic duct within one hour after death and then in vivo if a feasible technic could be developed (7). Volumetric measurements of the flow of lymph in addition would permit an estimation of the number of cells delivered per unit time into the peripheral circulation via the thoracic duct (8). Since at least two thoracic ducts are present in man in addition to innumerable other lymph-to-blood connections, it was realized that these anatomical considerations seriously limited the interpretation of single samples. Consequently cannulation of the major thoracic duct for continuous drainage over prolonged periods was undertaken.
- Published
- 1953
11. Effects of Short-Term Exposure to Dispersed Oil in Arctic Invertebrates
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C. Mageau, Edward S. Gilfillan, F.R. Engelhardt, and P.D. Boehm
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chemistry.chemical_classification ,Ecology ,Biodegradation ,Dispersant ,Marine pollution ,chemistry.chemical_compound ,Hydrocarbon ,chemistry ,Arctic ,Benthic zone ,Environmental chemistry ,Petroleum ,Ecology, Evolution, Behavior and Systematics ,Invertebrate - Abstract
A series of experimental studies was carried out as part of the Baffin Island Oil Spill (BIOS) Project to define the behavioural, physiological and biochemical reactions of three arctic marine benthic invertebrate species exposed to chemically dispersed crude oil. Behavioural responses and patterns of hydrocarbon accumulation and release observed in the bivalves and the urchin during the 1981 field spill were similar to those observed during the laboratory simulations. Ostial closure, loss of responsiveness to mechanical stimuli and narcosis were characteristic of the bivalves. Exposed urchins displayed a functional loss of tube foot and spine behaviour. Detailed hydrocarbon analysis indicated different uptake dynamics among the species. The effects of dispersed oil were immediate and short lived and resulted in temporary accumulation of hydrocarbons. Depuration of these stored hydrocarbons occurred during the experimental recovery period. In vivo biodegradation of hydrocarbons was indicated in the bivalves. Physiological parameters measured in bivalves exposed to oil included elements of scope for growth, activity of aspartate aminotransferase and glucose-6-phosphate dehydrogenase. Dose-response relationships between physiological rates and hydrocarbon body burden were apparent. Key words: petroleum effects, Arctic, invertebrates, metabolism, enzymes, behaviour, biodegradation, hydrocarbon uptake, Baffin Island oil spill, dispersant
- Published
- 1987
12. Feeding, Respiration and Excretion of the Copepod Calanus hyperboreus from Baffin Bay, Including Waters Contaminated by Oil Seeps
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John H. Vandermeulen, Edward S. Gilfillan, and Sherry Hanson
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geography ,geography.geographical_feature_category ,biology ,Animal food ,Inlet ,biology.organism_classification ,Zooplankton ,Petroleum seep ,Oceanography ,Arctic ,Clearance rate ,Bay ,Ecology, Evolution, Behavior and Systematics ,Geology ,Copepod - Abstract
Metabolic processes in eastern arctic copepods Calanus hyperboreus were analyzed during the post-bloom period (August-September). Mixed adult and subadult copepods were collected from 12 stations in Baffin Bay (Davis Strait to Lancaster Sound) by trawling from 0-300 m. Measurements were made of clearance rate, O2-consumption and NH3 excretion. The cruise track included 6 stations in oil-seep contaminated waters of Scott Inlet and Buchan Gulf. Physiological parameters for populations of C. hyperboreus from the latter stations were compared with those from non-seep stations. Mean O2 consumption rates (0.309 - 0.907 µl O2 / mg dry wt / h) for all stations were similar to those described for Antarctic calanoid species but were higher than reported for more northern arctic waters. Mean ammonia excretion rates (0.023 - 0.071 µg N / mg dry wt / h) were somewhat lower than reported for comparable Antarctic species and were similar to values from other eastern arctic studies. O:N ratios for 11 of the 12 stations occupied ranged between 8.4 and 22.1, indicative of protein-based metabolism. The single exception was a High Arctic station with O:N ratio 43.6. Clearance rates were low to nonexistant for all stations. Most of the non-feeding values came from the Scott Inlet-Buchan Gulf region of western Baffin Bay. At those stations in this region a strong negative correlation (P
- Published
- 1986
13. Expression of T-cell receptor alpha-chain genes in transgenic mice
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Christopher C. Goodnow, Leslie J. Berg, B Fazekas de St Groth, F. Ivars, H J Garchon, Mark M. Davis, and S. Gilfillan
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Transcription, Genetic ,Macromolecular Substances ,Transgene ,T-Lymphocytes ,Receptors, Antigen, T-Cell ,Mice, Inbred Strains ,Mice, Transgenic ,Biology ,Transfection ,Mice ,Animals ,Receptor ,Enhancer ,Molecular Biology ,Alleles ,Cell Biology ,Flow Cytometry ,Molecular biology ,Allelic exclusion ,Thymocyte ,Blotting, Southern ,Genes ,Cell culture ,Alpha chain ,Pseudogenes ,Research Article - Abstract
To examine the influences responsible for shaping the T-cell repertoire in vivo, we have introduced T-cell receptors of defined specificity into mice. In this report, we analyze transgenic mice carrying a T-cell receptor alpha-chain gene from a pigeon cytochrome c-reactive T-cell line. A variant of this construct, which has the immunoglobulin heavy-chain enhancer inserted into the JC intron, was also introduced into mice. Addition of the enhancer increased the steady-state level of transgene-encoded mRNA three- to fivefold in cultured T cells, leading to a two- to threefold increase in surface expression. In vivo, the difference between these two constructs was even more significant, increasing the number of transgene-positive cells from approximately 5 to 70% and the T-cell receptor surface density two- to threefold. Surprisingly, while surface expression of either type of transgene was limited to T cells, we found little tissue specificity with respect to transcription. In T cells expressing the alpha chain from the enhancer-containing construct, immunoprecipitation with a 2B4 alpha-specific monoclonal antibody revealed the expected disulfide-linked dimer. Costaining of these T cells with the 2B4 alpha-specific monoclonal antibody versus anti-CD3 indicated that expression of the transgene-encoded alpha chain precludes expression of endogenous alpha chains on the majority of cells; in contrast, 2B4 alpha-chain expression from the construct lacking the enhancer is inefficient at suppressing endogenous alpha-chain expression. In mice of the enhancer lineage, Southern blot analysis indicated suppression of endogenous alpha-chain rearrangements in T-cell populations, consistent with the observed allelic exclusion at the cellular level. Interestingly, newborn, but not adult, mice of this lineage also showed an increase in retention of unrearranged delta-chain loci in thymocyte DNA, presumably resulting from the suppression of alpha-chain rearrangements. This observation indicates that at least a fraction of alpha:beta-positive T cells have never attempted to produce functional delta rearrangements, thus suggesting that alpha:beta and gamma:delta T cells may be derived from different T-cell compartments (at least during the early phases of T-cell differentiation).
- Published
- 1988
14. Investigation of spontaneous vasomotor activity. Relation of the sympathetic and somatic nervous systems to the occurrence of slow waves (alpha and beta) of the plethysmogram of the dog's paw
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Rutherford S. Gilfillan, Elizabeth M. Cuthbertson, Richard D. Bruga, and Mikel Duino
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Denervation ,medicine.medical_specialty ,Chemoreceptor ,Sympathetic Nervous System ,Vasomotor ,Physiology ,Chemistry ,Alpha (ethology) ,Adrenergic ,Alpha wave ,Nervous System ,Plethysmography ,Endocrinology ,Dogs ,Anesthesia ,Internal medicine ,medicine ,Plethysmograph ,Animals ,Blood Vessels ,Nervous System Physiological Phenomena ,Beta wave ,Cardiology and Cardiovascular Medicine - Abstract
Spontaneous vasomotor activity, as evidenced by the presence of alpha or beta waves in the paw plethysmogram, was demonstrated in 10 sympathectomized, 4 denervated, and 8 (ganglionic or adrenergic) blockaded extremities in dogs. Alpha waves occur during natural sleep and during anesthesia. They are present after removal and denervation of the carotid and aortic chemoreceptors. They occur in the splenectoinized animal. Alpha waves are usually synchronous in a pair of normally innerverted extremities. They may be synchronous, asynchronous, or absent in one paw when one extremity (or both) is denervated or sympathectomized. The significance of this information is discussed in relation to the factors which may control spontaneous vasomotor activity.
- Published
- 1960
15. The Valsalva Maneuver: An Aid for the Contrast Visualization of the Aorta and Great Vessels
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N E, Freeman, T M, Fullenlove, E J, Wylie, and R S, Gilfillan
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Articles - Published
- 1949
16. A test for evaluating pedal gangrenous lesions: observation of elevation reactive hyperemia as a gauge of blood supply
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R S, GILFILLAN
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Gangrene ,Peripheral Vascular Diseases ,Wound Healing ,Foot ,Pressure ,food and beverages ,Humans ,Hyperemia ,Articles ,Toes ,Prognosis ,Amputation, Surgical - Abstract
Estimating the development of collateral circulation in peripheral vascular diseases is simplified by the use of an easy test-which can be done in an office-in which reactive hyperemia is observed in an extremity as it is gradually lowered after a period of elevation. The lower limits of filling pressures necessary to allow spontaneous healing of necrotic lesions under the conditions described seem to be in the range 35 cm. above the heart. Similarly the lower limit for the successful performance of amputations at the level of the forefoot or toes seems to be about 45 cm. As a result of over a thousand observations in a period of over five years, it is believed that the test provides in a few minutes a visual and reproducible picture of the filling pressures in the distal portions of the extremity which is useful in the determination of prognosis and the selection of treatment of gangrenous lesions of the foot.
- Published
- 1958
17. Bypass surgery mortality is blunt measure of performance.
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S, Gilfillan Ian
- Published
- 2004
18. Ranking heart surgeons has pitfalls.
- Author
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S, Gilfillan Ian
- Published
- 2003
19. The centrosomal protein FGFR1OP controls myosin function in murine intestinal epithelial cells.
- Author
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Trsan T, Peng V, Krishna C, Ohara TE, Beatty WL, Sudan R, Kanai M, Krishnamoorthy P, Rodrigues PF, Fachi JL, Grajales-Reyes G, Jaeger N, Fitzpatrick JAJ, Cella M, Gilfillan S, Nakata T, Jaiswal A, Stappenbeck TS, Daly MJ, Xavier RJ, and Colonna M
- Subjects
- Animals, Mice, Colitis metabolism, Colitis pathology, Colitis chemically induced, Colitis genetics, Centrosome metabolism, Humans, Cell Adhesion, Mice, Inbred C57BL, Crohn Disease metabolism, Crohn Disease pathology, Crohn Disease genetics, Actomyosin metabolism, Inflammation metabolism, Inflammation pathology, Inflammation genetics, Epithelial Cells metabolism, Intestinal Mucosa metabolism, Myosin Type II metabolism, Myosin Type II genetics
- Abstract
Recent advances in human genetics have shed light on the genetic factors contributing to inflammatory diseases, particularly Crohn's disease (CD), a prominent form of inflammatory bowel disease. Certain risk genes associated with CD directly influence cytokine biology and cell-specific communication networks. Current CD therapies primarily rely on anti-inflammatory drugs, which are inconsistently effective and lack strategies for promoting epithelial restoration and mucosal balance. To understand CD's underlying mechanisms, we investigated the link between CD and the FGFR1OP gene, which encodes a centrosome protein. FGFR1OP deletion in mouse intestinal epithelial cells disrupted crypt architecture, resulting in crypt loss, inflammation, and fatality. FGFR1OP insufficiency hindered epithelial resilience during colitis. FGFR1OP was crucial for preserving non-muscle myosin II activity, ensuring the integrity of the actomyosin cytoskeleton and crypt cell adhesion. This role of FGFR1OP suggests that its deficiency in genetically predisposed individuals may reduce epithelial renewal capacity, heightening susceptibility to inflammation and disease., Competing Interests: Declaration of interests R.J.X. is co-founder of Jnana Therapeutics and Celsius Therapeutics, scientific advisory board member at Nestlé, and board director at MoonLake Immunotherapeutics. These organizations had no roles in this study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
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20. A Cre-deleter specific for embryo-derived brain macrophages reveals distinct features of microglia and border macrophages.
- Author
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Brioschi S, Belk JA, Peng V, Molgora M, Rodrigues PF, Nguyen KM, Wang S, Du S, Wang WL, Grajales-Reyes GE, Ponce JM, Yuede CM, Li Q, Baer JM, DeNardo DG, Gilfillan S, Cella M, Satpathy AT, and Colonna M
- Subjects
- Mice, Animals, Integrases genetics, Integrases metabolism, Brain metabolism, Microglia metabolism, Macrophages metabolism
- Abstract
Genetic tools to target microglia specifically and efficiently from the early stages of embryonic development are lacking. We generated a constitutive Cre line controlled by the microglia signature gene Crybb1 that produced nearly complete recombination in embryonic brain macrophages (microglia and border-associated macrophages [BAMs]) by the perinatal period, with limited recombination in peripheral myeloid cells. Using this tool in combination with Flt3-Cre lineage tracer, single-cell RNA-sequencing analysis, and confocal imaging, we resolved embryonic-derived versus monocyte-derived BAMs in the mouse cortex. Deletion of the transcription factor SMAD4 in microglia and embryonic-derived BAMs using Crybb1-Cre caused a developmental arrest of microglia, which instead acquired a BAM specification signature. By contrast, the development of genuine BAMs remained unaffected. Our results reveal that SMAD4 drives a transcriptional and epigenetic program that is indispensable for the commitment of brain macrophages to the microglia fate and highlight Crybb1-Cre as a tool for targeting embryonic brain macrophages., Competing Interests: Declaration of interests A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
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21. Transcriptomic atlas and interaction networks of brain cells in mouse CNS demyelination and remyelination.
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Hou J, Zhou Y, Cai Z, Terekhova M, Swain A, Andhey PS, Guimaraes RM, Ulezko Antonova A, Qiu T, Sviben S, Strout G, Fitzpatrick JAJ, Chen Y, Gilfillan S, Kim DH, Van Dyken SJ, Artyomov MN, and Colonna M
- Subjects
- Animals, Mice, Transcriptome genetics, Brain metabolism, Oligodendroglia metabolism, Microglia metabolism, Cuprizone toxicity, Disease Models, Animal, Mice, Inbred C57BL, Myelin Sheath metabolism, Demyelinating Diseases metabolism, Remyelination
- Abstract
Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFB
hi microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases., Competing Interests: Declaration of interests M.C. is a member of the scientific advisory board of Vigil, receives research support from Vigil, and is a consultant for CST., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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22. Repression of the aryl-hydrocarbon receptor prevents oxidative stress and ferroptosis of intestinal intraepithelial lymphocytes.
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Panda SK, Peng V, Sudan R, Ulezko Antonova A, Di Luccia B, Ohara TE, Fachi JL, Grajales-Reyes GE, Jaeger N, Trsan T, Gilfillan S, Cella M, and Colonna M
- Subjects
- Animals, Mice, Repressor Proteins genetics, Repressor Proteins metabolism, Receptors, Aryl Hydrocarbon genetics, Receptors, Aryl Hydrocarbon metabolism, Basic Helix-Loop-Helix Transcription Factors metabolism, Oxidative Stress, Hydrocarbons, Ferroptosis, Intraepithelial Lymphocytes metabolism
- Abstract
The aryl-hydrocarbon receptor (AHR) is a ligand-activated transcription factor that buoys intestinal immune responses. AHR induces its own negative regulator, the AHR repressor (AHRR). Here, we show that AHRR is vital to sustaining intestinal intraepithelial lymphocytes (IELs). AHRR deficiency reduced IEL representation in a cell-intrinsic fashion. Single-cell RNA sequencing revealed an oxidative stress profile in Ahrr
-/- IELs. AHRR deficiency unleashed AHR-induced expression of CYP1A1, a monooxygenase that generates reactive oxygen species, increasing redox imbalance, lipid peroxidation, and ferroptosis in Ahrr-/- IELs. Dietary supplementation with selenium or vitamin E to restore redox homeostasis rescued Ahrr-/- IELs. Loss of IELs in Ahrr-/- mice caused susceptibility to Clostridium difficile infection and dextran sodium-sulfate-induced colitis. Inflamed tissue of inflammatory bowel disease patients showed reduced Ahrr expression that may contribute to disease. We conclude that AHR signaling must be tightly regulated to prevent oxidative stress and ferroptosis of IELs and to preserve intestinal immune responses., Competing Interests: Declaration of interests M. Colonna receives research support from Pfizer., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
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23. SLC7A8 is a key amino acids supplier for the metabolic programs that sustain homeostasis and activation of type 2 innate lymphoid cells.
- Author
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Panda SK, Kim DH, Desai P, Rodrigues PF, Sudan R, Gilfillan S, Cella M, Van Dyken SJ, and Colonna M
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- Interleukin-13 genetics, Amino Acids, Proto-Oncogene Proteins c-myc metabolism, Signal Transduction, Homeostasis, Arginine, Cytokines metabolism, Interleukin-33, Lung metabolism, Immunity, Innate, Lymphocytes
- Abstract
Group 2 innate lymphoid cells (ILC2) are innate counterparts of T helper 2 (Th2) cells that maintain tissue homeostasis and respond to injuries through rapid interleukin (IL)-5 and IL-13 secretion. ILC2s depend on availability of arginine and branched-chain amino acids for sustaining cellular fitness, proliferation, and cytokine secretion in both steady state and upon activation. However, the contribution of amino acid transporters to ILC2 functions is not known. Here, we found that ILC2s selectively express Slc7a8 , encoding a transporter for arginine and large amino acids. Slc7a8 was expressed in ILC2s in a tissue-specific manner in steady state and was further increased upon activation. Genetic ablation of Slc7a8 in lymphocytes reduced the frequency of ILC2s, suppressed IL-5 and IL-13 production upon stimulation, and impaired type 2 immune responses to helminth infection. Consistent with this, Slc7a8- deficient ILC2s also failed to induce cytokine production and recruit eosinophils in a model of allergic lung inflammation. Mechanistically, reduced amino acid availability due to Slc7a8 deficiency led to compromised mitochondrial oxidative phosphorylation, as well as impaired activation of mammalian target of rapamycin and c-Myc signaling pathways. These findings identify Slc7a8 as a key supplier of amino acids for the metabolic programs underpinning fitness and activation of ILC2s.
- Published
- 2022
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24. TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways.
- Author
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Wang S, Sudan R, Peng V, Zhou Y, Du S, Yuede CM, Lei T, Hou J, Cai Z, Cella M, Nguyen K, Poliani PL, Beatty WL, Chen Y, Cao S, Lin K, Rodrigues C, Ellebedy AH, Gilfillan S, Brown GD, Holtzman DM, Brioschi S, and Colonna M
- Subjects
- Animals, Mice, Humans, Glycogen Synthase Kinase 3 beta metabolism, Phosphatidylinositol 3-Kinases metabolism, Amyloid beta-Peptides metabolism, Plaque, Amyloid metabolism, Brain metabolism, Disease Models, Animal, Syk Kinase metabolism, Membrane Glycoproteins genetics, Membrane Glycoproteins metabolism, Receptors, Immunologic metabolism, Microglia metabolism, Alzheimer Disease pathology
- Abstract
Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Aβ plaques acquire a transcriptional signature, "disease-associated microglia" (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2
R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aβ plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK-3β-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adapter DAP10, which also binds TREM2. Thus, microglial responses to Aβ involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy., Competing Interests: Declaration of interests M. Colonna is a member of Vigil Neuro scientific advisory board (SAB), is consultant for Cell Signaling Technology and NGM Bio, has received research grants from Vigil Neuro during the conduct of the study, and has a patent to TREM2 pending. DMH co-founded and is on the SAB of C2N Diagnostics; is on the SAB of Denali, Genentech, and Cajal Neuroscience; consults for Alector; and is on the Advisory Board for Cell., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2022
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25. The aryl hydrocarbon receptor instructs the immunomodulatory profile of a subset of Clec4a4 + eosinophils unique to the small intestine.
- Author
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Wang WL, Kasamatsu J, Joshita S, Gilfillan S, Di Luccia B, Panda SK, Kim DH, Desai P, Bando JK, Huang SC, Yomogida K, Hoshino H, Fukushima M, Jacobsen EA, Van Dyken SJ, Ruedl C, Cella M, and Colonna M
- Subjects
- Eosinophilia therapy, Food Hypersensitivity therapy, Immunomodulation, Intestine, Small, Leukocyte Count, Ligands, Eosinophils, Receptors, Aryl Hydrocarbon genetics, Receptors, Cell Surface
- Abstract
C-type lectin domain family 4, member a4 (Clec4a4) is a C-type lectin inhibitory receptor specific for glycans thought to be exclusively expressed on murine CD8α− conventional dendritic cells. Using newly generated Clec4a4-mCherry knock-in mice, we identify a subset of Clec4a4-expressing eosinophils uniquely localized in the small intestine lamina propria. Clec4a4+ eosinophils evinced an immunomodulatory signature, whereas Clec4a4− eosinophils manifested a proinflammatory profile. Clec4a4+ eosinophils expressed high levels of aryl hydrocarbon receptor (Ahr), which drove the expression of Clec4a4 as well as other immunomodulatory features, such as PD-L1. The abundance of Clec4a4+ eosinophils was dependent on dietary AHR ligands, increased with aging, and declined in inflammatory conditions. Mice lacking AHR in eosinophils expanded innate lymphoid cells of type 2 and cleared Nippostrongylus brasiliensis infection more effectively than did wild-type mice. These results highlight the heterogeneity of eosinophils in response to tissue cues and identify a unique AHR-dependent subset of eosinophils in the small intestine with an immunomodulatory profile.
- Published
- 2022
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26. Hobit confers tissue-dependent programs to type 1 innate lymphoid cells.
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Yomogida K, Bigley TM, Trsan T, Gilfillan S, Cella M, Yokoyama WM, Egawa T, and Colonna M
- Subjects
- Animals, Antigens, CD, Biomarkers, Gene Deletion, Gene Expression Regulation physiology, Granzymes genetics, Granzymes metabolism, Interferon-gamma genetics, Interferon-gamma metabolism, Liver metabolism, Membrane Proteins genetics, Mice, RNA, Small Cytoplasmic genetics, RNA, Small Cytoplasmic metabolism, RNA-Seq, T-Box Domain Proteins genetics, Transcription Factors genetics, Immunity, Cellular physiology, Immunity, Innate physiology, Lymphocyte Subsets classification, Lymphocyte Subsets physiology, T-Box Domain Proteins metabolism, Transcription Factors metabolism
- Abstract
Identification of type 1 innate lymphoid cells (ILC1s) has been problematic. The transcription factor Hobit encoded by Zfp683 has been proposed as a major driver of ILC1 programs. Using Zfp683 reporter mice, we showed that correlation of Hobit expression with ILC1s is tissue- and context-dependent. In liver and intestinal mucosa, Zfp683 expression correlated well with ILC1s; in salivary glands, Zfp683 was coexpressed with the natural killer (NK) master transcription factors Eomes and TCF1 in a unique cell population, which we call ILC1-like NK cells; during viral infection, Zfp683 was induced in conventional NK cells of spleen and liver. The impact of Zfp683 deletion on ILC1s and NK cells was also multifaceted, including a marked decrease in granzyme- and interferon-gamma (IFNγ)-producing ILC1s in the liver, slightly fewer ILC1s and more Eomes
+ TCF1+ ILC1-like NK cells in salivary glands, and only reduced production of granzyme B by ILC1 in the intestinal mucosa. NK cell-mediated control of viral infection was unaffected. We conclude that Hobit has two major impacts on ILC1s: It sustains liver ILC1 numbers, while promoting ILC1 functional maturation in other tissues by controlling TCF1, Eomes, and granzyme expression., Competing Interests: The authors declare no competing interest.- Published
- 2021
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27. Spatial distribution of LTi-like cells in intestinal mucosa regulates type 3 innate immunity.
- Author
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Sécca C, Bando JK, Fachi JL, Gilfillan S, Peng V, Di Luccia B, Cella M, McDonald KG, Newberry RD, and Colonna M
- Subjects
- Animals, Gene Deletion, Interleukin-17 genetics, Interleukins genetics, Intestinal Mucosa cytology, Lymphocytes cytology, Mice, Mice, Knockout, Receptors, CXCR5 genetics, Interleukin-22, Immunity, Innate, Interleukin-17 immunology, Interleukins immunology, Intestinal Mucosa immunology, Lymphocytes immunology, Receptors, CXCR5 immunology
- Abstract
Lymphoid tissue inducer (LTi)-like cells are tissue resident innate lymphocytes that rapidly secrete cytokines that promote gut epithelial integrity and protect against extracellular bacterial infections.Here, we report that the retention of LTi-like cells in conventional solitary intestinal lymphoid tissue (SILT) is essential for controlling LTi-like cell function and is maintained by expression of the chemokine receptor CXCR5. Deletion of Cxcr5 functionally unleashed LTi-like cells in a cell intrinsic manner, leading to uncontrolled IL-17 and IL-22 production. The elevated production of IL-22 in Cxcr5 -deficient mice improved gut barrier integrity and protected mice during infection with the opportunistic pathogen Clostridium difficile Interestingly, Cxcr5
-/- mice developed LTi-like cell aggregates that were displaced from their typical niche at the intestinal crypt, and LTi-like cell hyperresponsiveness was associated with the local formation of this unconventional SILT. Thus, LTi-like cell positioning within mucosa controls their activity via niche-specific signals that temper cytokine production during homeostasis., Competing Interests: Competing interest statement: M. Colonna receives research support from Pfizer.- Published
- 2021
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28. Altered ratio of dendritic cell subsets in skin-draining lymph nodes promotes Th2-driven contact hypersensitivity.
- Author
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Miller HL, Andhey PS, Swiecki MK, Rosa BA, Zaitsev K, Villani AC, Mitreva M, Artyomov MN, Gilfillan S, Cella M, and Colonna M
- Subjects
- Animals, Antigens, CD genetics, Antigens, CD immunology, Cell Lineage genetics, Cell Lineage immunology, Dermatitis, Contact genetics, Dermatitis, Contact pathology, Diphtheria Toxin genetics, Heparin-binding EGF-like Growth Factor genetics, Heparin-binding EGF-like Growth Factor immunology, Humans, Integrin alpha Chains genetics, Integrin alpha Chains immunology, Lymph Nodes immunology, Mice, Mice, Inbred C57BL, Promoter Regions, Genetic genetics, Th2 Cells immunology, Transcription Factor 4 genetics, Transcription Factor 4 immunology, Dendritic Cells immunology, Dermatitis, Contact immunology, Interferon Type I genetics, Lectins, C-Type genetics, Receptors, Immunologic genetics, Skin immunology
- Abstract
Plasmacytoid dendritic cells (pDCs) specialize in the production of type I IFN (IFN-I). pDCs can be depleted in vivo by injecting diphtheria toxin (DT) in a mouse in which pDCs express a diphtheria toxin receptor (DTR) transgene driven by the human CLEC4C promoter. This promoter is enriched for binding sites for TCF4, a transcription factor that promotes pDC differentiation and expression of pDC markers, including CLEC4C. Here, we found that injection of DT in CLEC4C-DTR
+ mice markedly augmented Th2-dependent skin inflammation in a model of contact hypersensitivity (CHS) induced by the hapten fluorescein isothiocyanate. Unexpectedly, this biased Th2 response was independent of reduced IFN-I accompanying pDC depletion. In fact, DT treatment altered the representation of conventional dendritic cells (cDCs) in the skin-draining lymph nodes during the sensitization phase of CHS; there were fewer Th1-priming CD326+ CD103+ cDC1 and more Th2-priming CD11b+ cDC2. Single-cell RNA-sequencing of CLEC4C-DTR+ cDCs revealed that CD326+ DCs, like pDCs, expressed DTR and were depleted together with pDCs by DT treatment. Since CD326+ DCs did not express Tcf4 , DTR expression might be driven by yet-undefined transcription factors activating the CLEC4C promoter. These results demonstrate that altered DC representation in the skin-draining lymph nodes during sensitization to allergens can cause Th2-driven CHS., Competing Interests: Competing interest statement: M.K.S., a former post-doc of the Colonna laboratory, is now an employee of Janssen Research & Development.- Published
- 2021
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29. Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease.
- Author
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Ellwanger DC, Wang S, Brioschi S, Shao Z, Green L, Case R, Yoo D, Weishuhn D, Rathanaswami P, Bradley J, Rao S, Cha D, Luan P, Sambashivan S, Gilfillan S, Hasson SA, Foltz IN, van Lookeren Campagne M, and Colonna M
- Subjects
- Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Peptides genetics, Amyloid beta-Peptides metabolism, Animals, Antibodies, Monoclonal pharmacology, Antibodies, Neutralizing pharmacology, Brain drug effects, Brain pathology, Cell Proliferation, Chemokines genetics, Chemokines metabolism, Disease Models, Animal, Female, Gene Expression Regulation, HEK293 Cells, Humans, Kinetics, Male, Membrane Glycoproteins antagonists & inhibitors, Membrane Glycoproteins metabolism, Mice, Mice, Transgenic, Microglia classification, Microglia drug effects, Microglia pathology, Mutation, Protein Binding, Receptors, Immunologic antagonists & inhibitors, Receptors, Immunologic metabolism, Sex Factors, Alzheimer Disease genetics, Brain metabolism, Membrane Glycoproteins genetics, Microglia metabolism, Receptors, Immunologic genetics
- Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid β (Aβ). Alzheimer's disease (AD) risk is associated with the TREM2
R47H variant, which impairs ligand binding and consequently microglia responses to Aβ pathology. Here, we show that TREM2 engagement by the mAb hT2AB as surrogate ligand activates microglia in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant ( TREM2CV ) or TREM2R47H scRNA-seq of microglia from TREM2CV -5XFAD mice treated once with control hIgG1 exposed four distinct trajectories of microglia activation leading to disease-associated (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia types. All of these were underrepresented in TREM2R47H -5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia activation trajectories. Moreover, Cyc-M and IFN-R microglia were more abundant in female than male TREM2CV -5XFAD mice, likely due to greater Aβ load in female 5XFAD mice. A single systemic injection of hT2AB replenished Cyc-M, IFN-R, and MHC-II pools in TREM2R47H -5XFAD mice. In TREM2CV -5XFAD mice, however, hT2AB brought the representation of male Cyc-M and IFN-R microglia closer to that of females, in which these trajectories had already reached maximum capacity. Moreover, hT2AB induced shifts in gene expression patterns in all microglial pools without affecting representation. Repeated treatment with a murinized hT2AB version over 10 d increased chemokines brain content in TREM2R47H -5XFAD mice, consistent with microglia expansion. Thus, the impact of hT2AB on microglia is shaped by the extent of TREM2 endogenous ligand engagement and basal microglia activation., Competing Interests: Competing interest statement: D.C.E., Z.S., L.G., R.C., D.Y., D.W., P.R., J.B., S.R., D.C., P.L., S.S., S.A.H., I.N.F., and M.v.L.C. are current employees or were past Amgen employees at the time when the experiments were performed. S.S. is Vice President of Nura Bio Inc. M.C. received research support from Amgen and serves on the Scientific Advisory Board of Vigil Neuroscience Inc.- Published
- 2021
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30. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model.
- Author
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Wang S, Mustafa M, Yuede CM, Salazar SV, Kong P, Long H, Ward M, Siddiqui O, Paul R, Gilfillan S, Ibrahim A, Rhinn H, Tassi I, Rosenthal A, Schwabe T, and Colonna M
- Subjects
- Alzheimer Disease cerebrospinal fluid, Amyloid beta-Peptides chemistry, Amyloid beta-Peptides metabolism, Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Anxiety pathology, Biomarkers cerebrospinal fluid, Blood-Brain Barrier drug effects, Blood-Brain Barrier pathology, Cell Proliferation drug effects, Disease Models, Animal, Humans, Membrane Glycoproteins immunology, Mice, Inbred C57BL, Mice, Transgenic, Microglia drug effects, Microglia metabolism, Neurites drug effects, Neurites pathology, Osteopontin metabolism, Protein Conformation, Receptors, Immunologic immunology, Signal Transduction, Solubility, Alzheimer Disease pathology, Alzheimer Disease therapy, Membrane Glycoproteins metabolism, Microglia pathology, Receptors, Immunologic metabolism
- Abstract
TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer's disease (AD) risk. In mouse models of amyloid β (Aβ) accumulation, defective TREM2 function affects microglial response to Aβ plaques, exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single-cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior, and tempered microglial inflammatory response. We further showed that a variant of AL002c is safe and well tolerated in a first-in-human phase I clinical trial and engages TREM2 based on cerebrospinal fluid biomarkers. We conclude that AL002 is a promising candidate for AD therapy., Competing Interests: Disclosures: M. Mustafa, S.V. Salazar, P. Kong, H. Long, M. Ward, O. Siddiqui, R. Paul, A. Ibrahim, H. Rhinn, I. Tassi, A. Rosenthal, and T. Schwabe reported "other" from Alector, Inc. during the conduct of the study. The authors are employees of Alector LLC and may have an equity interest in Alector, Inc. Alector and AbbVie are parties to an agreement relating to the development and commercialization of AL002. M. Colonna reported "other" from Alector and grants from Alector, Amgen, and Ono during the conduct of the study. In addition, Alector LLC has pending patent applications and M. Colonna has a patent to TREM2 pending. No other disclosures were reported., (© 2020 Wang et al.)
- Published
- 2020
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31. TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy.
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Molgora M, Esaulova E, Vermi W, Hou J, Chen Y, Luo J, Brioschi S, Bugatti M, Omodei AS, Ricci B, Fronick C, Panda SK, Takeuchi Y, Gubin MM, Faccio R, Cella M, Gilfillan S, Unanue ER, Artyomov MN, Schreiber RD, and Colonna M
- Subjects
- Animals, Antibodies, Monoclonal therapeutic use, CX3C Chemokine Receptor 1 metabolism, Cell Line, Tumor, Disease Models, Animal, Humans, Lymphocytes, Tumor-Infiltrating cytology, Lymphocytes, Tumor-Infiltrating metabolism, Membrane Glycoproteins deficiency, Membrane Glycoproteins genetics, Methylcholanthrene toxicity, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplasms chemically induced, Neoplasms pathology, Prognosis, Programmed Cell Death 1 Receptor metabolism, Receptors, Immunologic deficiency, Receptors, Immunologic genetics, Tumor Microenvironment, Immunotherapy, Membrane Glycoproteins metabolism, Neoplasms therapy, Programmed Cell Death 1 Receptor immunology, Receptors, Immunologic metabolism
- Abstract
Checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells. TREM2 is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer's disease. TREM2 is also expressed by tumor-infiltrating macrophages. Here, we found that Trem2
-/- mice are more resistant to growth of various cancers than wild-type mice and are more responsive to anti-PD-1 immunotherapy. Furthermore, treatment with anti-TREM2 mAb curbed tumor growth and fostered regression when combined with anti-PD-1. scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1+ and CX3 CR1+ macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses. TREM2 was expressed in tumor macrophages in over 200 human cancer cases and inversely correlated with prolonged survival for two types of cancer. Thus, TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy., Competing Interests: Declaration of Interests M. Colonna received research support from Alector, Amgen, Ono, and Pfizer for activities not related to the findings described in this publication. M. Colonna is a scientific advisory board member of Alector, Cell Signaling Technologies, and Bluefin, and has a patent to TREM2 pending. R.D.S. is a cofounder, scientific advisory board member, stockholder, and royalty recipient of Jounce Therapeutics and Neon Therapeutics and is a scientific advisory board member for A2 Biotherapeutics, BioLegend, Codiak Biosciences, Constellation Pharmaceuticals, NGM Biopharmaceuticals, and Sensei Biotherapeutics., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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32. Author Correction: Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.
- Author
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Zhou Y, Song WM, Andhey PS, Swain A, Levy T, Miller KR, Poliani PL, Cominelli M, Grover S, Gilfillan S, Cella M, Ulland TK, Zaitsev K, Miyashita A, Ikeuchi T, Sainouchi M, Kakita A, Bennett DA, Schneider JA, Nichols MR, Beausoleil SA, Ulrich JD, Holtzman DM, Artyomov MN, and Colonna M
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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33. Implementing an mhGAP-based training and supervision package to improve healthcare workers' competencies and access to mental health care in Malawi.
- Author
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Ahrens J, Kokota D, Mafuta C, Konyani M, Chasweka D, Mwale O, Stewart RC, Osborn M, Chikasema B, Mcheka M, Blackwood D, and Gilfillan S
- Abstract
Background: It is now well established that the integration of mental health care into primary care is one of the most effective ways of reducing the substantial treatment gap for mental disorders which exists in most low- and middle-income countries. This study set out to determine whether a Mental Health Gap Action Programme (mhGAP) training and supervision package could be contextualised and implemented within the existing health care system in five districts in Southern Malawi. In addition, the study assessed the feasibility of holding community awareness events and establishing peer support groups in each district to further improve the access of the population to evidence-based mental health care., Methods: A lead training team of experienced Malawian mental health professionals was appointed and mhGAP training materials were contextualised for use in Malawi. The lead team delivered a 4-day training package to district mental health teams in five districts covering three core conditions: psychosis, moderate-severe depression, and alcohol and substance use disorders. District mental health teams then delivered a 2-day training package and provided monthly supervision for 3 months to 500 non-specialist healthcare workers. Paired sample t-tests were used to compare knowledge, confidence and attitude scores before and immediately after training, and after 6 months in two districts. Case detection rates measured pre- and post-training in the pilot district were compared using Wilcoxon Rank Sum Test. Community awareness events were held and peer support groups were established in each of the five districts. The acceptability of the package was assessed through focus group discussions involving specialist and non-specialist healthcare workers, users and carers., Results: Non-specialist healthcare workers' knowledge and confidence scores significantly increased immediately after training in comparison to pre-training. These scores were maintained at 6 months. However, no statistically significant change in attitude scores was detected. Case detection rates increased immediately after the training in comparison to pre-training. Responses from focus group discussion participants illustrated the programme's acceptability., Conclusions: This study demonstrated that, with minimal additional funding and working within existing structures, an mhGAP based training at primary and secondary health care levels is feasible in Southern Malawi., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)
- Published
- 2020
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34. ILC2s are the predominant source of intestinal ILC-derived IL-10.
- Author
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Bando JK, Gilfillan S, Di Luccia B, Fachi JL, Sécca C, Cella M, and Colonna M
- Subjects
- Animals, Cells, Cultured, Citrobacter rodentium, Colitis chemically induced, Colitis immunology, Colitis pathology, Dextran Sulfate pharmacology, Disease Models, Animal, Enterobacteriaceae Infections immunology, Enterobacteriaceae Infections microbiology, Enterobacteriaceae Infections pathology, Feedback, Physiological, Female, Genes, Reporter, Green Fluorescent Proteins genetics, Interleukin-10 genetics, Male, Mice, Mice, Inbred C57BL, Neuropeptides metabolism, Tumor Necrosis Factor Ligand Superfamily Member 15 metabolism, Immunity, Innate, Interleukin-10 metabolism, Intestinal Mucosa cytology, Intestinal Mucosa pathology, T-Lymphocytes, Regulatory immunology
- Abstract
Although innate lymphoid cells (ILCs) functionally analogous to T helper type 1 (Th1), Th2, and Th17 cells are well characterized, an ILC subset strictly equivalent to IL-10-secreting regulatory T cells has only recently been proposed. Here, we report the absence of an intestinal regulatory ILC population distinct from group 1 ILCs (ILC1s), ILC2s, and ILC3s in (1) mice bred in our animal facility; (2) mice from The Jackson Laboratory, Taconic Biosciences, and Charles River Laboratories; and (3) mice subjected to intestinal inflammation. Instead, a low percentage of intestinal ILC2s produced IL-10 at steady state. A screen for putative IL-10 elicitors revealed that IL-2, IL-4, IL-27, IL-10, and neuromedin U (NMU) increased IL-10 production in activated intestinal ILC2s, while TL1A suppressed IL-10 production. Secreted IL-10 further induced IL-10 production in ILC2s through a positive feedback loop. In summary, ILC2s provide an inducible source of IL-10 in the gastrointestinal tract, whereas ILCregs are not a generalizable immune cell population in mice., (© 2019 Bando et al.)
- Published
- 2020
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35. Evaluation of mhGAP training for primary healthcare workers in Mulanje, Malawi: a quasi-experimental and time series study.
- Author
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Kokota D, Lund C, Ahrens J, Breuer E, and Gilfillan S
- Abstract
Background: There has been a growing global movement championed by the World Health Organization (WHO) to integrate mental health into primary health care as the most effective way of reducing the mental health treatment gap. This study aimed to investigate the impact of WHO Mental Health Gap Action Programme (mhGAP) training and supervision on primary health workers' knowledge, confidence, attitudes and detection rate of major mental disorders in Mulanje, Malawi., Method: The study used a quasi-experimental method (single cohort pre- and post-measures) with an interrupted time-series design. A 2 day mhGAP training was delivered to 43 primary healthcare workers (PHWs) working in 18 primary care clinics serving the entire population of Mulanje, Malawi (population 684,107). Modules covered were psychosis, moderate-severe depression, and alcohol & substance use disorders. The PHWs completed pre and post-tests to assess knowledge, confidence and attitudes. Number of diagnosed cases was obtained from clinic registers for 5 months prior to and 7 months following training. Data was analyzed using mean scores, t-test, one-way analysis of variance and linear regression., Results: The mean knowledge score increased significantly from 11.8 (SD: 0.33) before training to 15.1 (SD: 0.38) immediately after training; t (42) = 7.79, p < 0.01. Similarly, mean knowledge score was significantly higher 6 months post training at 13.9 (SD: 2.52) compared to before; t (42) = 4.57, p < 0.01. The mean confidence score also increased significantly from 39.9 (SD: 7.68) before training to 49.6 (SD: 06.14) immediately after training; t (84) = 8.43, p < 0.01. It was also significantly higher 6 months post training 46.8, (SD: 6.03) compared to before; t (84) = 6.60, p < 0.01. One-way analysis of variance showed no significant difference in mean scores on all four components of the scale used to measure attitudes. A significant positive change in the trend in mental health service utilization after the intervention was demonstrated using a segmented linear regression (β = 2.43 (95% CI 1.02; 3.83) as compared to before (β = - 0.22 (95% CI - 2.67; 2.23) and immediately after (β = 1.63 (95% CI - 7.31; 10.57)., Conclusion: The findings of this study add to the growing evidence for policy makers of the effectiveness of mhGAP training and supervision in a resource-constrained country., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)
- Published
- 2020
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36. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.
- Author
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Zhou Y, Song WM, Andhey PS, Swain A, Levy T, Miller KR, Poliani PL, Cominelli M, Grover S, Gilfillan S, Cella M, Ulland TK, Zaitsev K, Miyashita A, Ikeuchi T, Sainouchi M, Kakita A, Bennett DA, Schneider JA, Nichols MR, Beausoleil SA, Ulrich JD, Holtzman DM, Artyomov MN, and Colonna M
- Subjects
- Aged, Amyloid beta-Peptides metabolism, Animals, Astrocytes metabolism, Astrocytes pathology, Axons pathology, Brain metabolism, Brain pathology, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Microglia metabolism, Microglia pathology, Middle Aged, Nerve Degeneration pathology, Oligodendroglia metabolism, Oligodendroglia pathology, Transcription, Genetic, Alzheimer Disease genetics, Alzheimer Disease pathology, Cell Nucleus metabolism, Cell Nucleus pathology, Membrane Glycoproteins metabolism, Receptors, Immunologic metabolism, Transcriptome genetics
- Abstract
Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n
+ C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.- Published
- 2020
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37. DC-SCRIPT deficiency delays mouse mammary gland development and branching morphogenesis.
- Author
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Tang C, van den Bijgaart RJE, Looman MWG, Tel-Karthaus N, de Graaf AMA, Gilfillan S, Colonna M, Ansems M, and Adema GJ
- Subjects
- Animals, Cell Culture Techniques methods, Cell Cycle Checkpoints genetics, DNA-Binding Proteins deficiency, Epithelial Cells metabolism, Epithelium growth & development, Epithelium metabolism, Female, Gene Expression Regulation, Developmental, Homeostasis genetics, Mammary Glands, Animal growth & development, Mice, Inbred C57BL, Mice, Knockout, Nuclear Proteins deficiency, Organoids cytology, Organoids growth & development, Transcription Factors deficiency, DNA-Binding Proteins genetics, Mammary Glands, Animal metabolism, Morphogenesis genetics, Nuclear Proteins genetics, Organoids metabolism, Transcription Factors genetics
- Abstract
Mammary glands are unique organs in which major adaptive changes occur in morphogenesis and development after birth. Breast cancer is the most common cancer and a major cause of mortality in females worldwide. We have previously identified the loss of expression of the transcription regulator DC-SCRIPT (Zfp366) as a prominent prognostic event in estrogen receptor positive breast cancer patients. DC-SCRIPT affects multiple transcriptional events in breast cancer cells, including estrogen and progesterone receptor-mediated transcription, and promotes CDKN2B-related cell cycle arrest. As loss of DC-SCRIPT expression appears an early event in breast cancer development, we here investigated the role of DC-SCRIPT in mammary gland development using wild-type and DC-SCRIPT knockout mice. Mice lacking DC-SCRIPT exhibited severe breeding problems and showed significant growth delay relative to littermate wild-type mice. Subsequent analysis revealed that DC-SCRIPT was expressed in mouse mammary epithelium and that DC-SCRIPT deficiency delayed mammary gland morphogenesis in vivo. Finally, analysis of 3D mammary gland organoid cultures confirmed that loss of DC-SCRIPT dramatically delayed mammary organoid branching in vitro. The study shows for the first time that DC-SCRIPT deficiency delays mammary gland morphogenesis in vivo and in vitro. These data define DC-SCRIPT as a novel modulator of mammary gland development., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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38. ILC3s integrate glycolysis and mitochondrial production of reactive oxygen species to fulfill activation demands.
- Author
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Di Luccia B, Gilfillan S, Cella M, Colonna M, and Huang SC
- Subjects
- Animals, Enterobacteriaceae Infections genetics, Enterobacteriaceae Infections pathology, Glycolysis genetics, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit immunology, Interleukin-17 genetics, Interleukin-17 immunology, Interleukins genetics, Interleukins immunology, Mechanistic Target of Rapamycin Complex 1 genetics, Mechanistic Target of Rapamycin Complex 1 immunology, Mice, Mice, Knockout, Mitochondria genetics, Mitochondria pathology, Nuclear Receptor Subfamily 1, Group F, Member 3 genetics, Nuclear Receptor Subfamily 1, Group F, Member 3 immunology, Th17 Cells pathology, Interleukin-22, Citrobacter rodentium immunology, Enterobacteriaceae Infections immunology, Glycolysis immunology, Lymphocyte Activation, Mitochondria immunology, Reactive Oxygen Species immunology, Th17 Cells immunology
- Abstract
Group 3 innate lymphoid cells (ILC3s) are the innate counterparts of Th17 that require the transcription factor RORγt for development and contribute to the defense against pathogens through IL-22 and IL-17 secretion. Proliferation and effector functions of Th17 require a specific mTOR-dependent metabolic program that utilizes high-rate glycolysis, while mitochondrial lipid oxidation and production of reactive oxygen species (mROS) support alternative T reg cell differentiation. Whether ILC3s employ a specific metabolic program is not known. Here, we find that ILC3s rely on mTOR complex 1 (mTORC1) for proliferation and production of IL-22 and IL-17A after in vitro activation and Citrobacter rodentium infection. mTORC1 induces activation of HIF1α, which reprograms ILC3 metabolism toward glycolysis and sustained expression of RORγt. However, in contrast to Th17, ILC3 activation requires mROS production; rather than inducing an alternative regulatory fate as it does in CD4 T cells, mROS stabilizes HIF1α and RORγt in ILC3s and thereby promotes their activation. We conclude that ILC3 activation relies on a metabolic program that integrates glycolysis with mROS production., (© 2019 Di Luccia et al.)
- Published
- 2019
- Full Text
- View/download PDF
39. CRTAM Protects Against Intestinal Dysbiosis During Pathogenic Parasitic Infection by Enabling Th17 Maturation.
- Author
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Cervantes-Barragan L, Cortez VS, Wang Q, McDonald KG, Chai JN, Di Luccia B, Gilfillan S, Hsieh CS, Newberry RD, Sibley LD, and Colonna M
- Subjects
- Animals, Cell Differentiation genetics, Dysbiosis immunology, Female, Immunoglobulins genetics, Intestinal Mucosa immunology, Intestinal Mucosa microbiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Toxoplasmosis, Animal parasitology, alpha-Defensins metabolism, beta-Defensins metabolism, Dysbiosis parasitology, Gastrointestinal Microbiome immunology, Immunoglobulins metabolism, Interleukin-17 metabolism, Th17 Cells immunology, Toxoplasma immunology, Toxoplasmosis, Animal immunology
- Abstract
The gastrointestinal tract hosts the largest collection of commensal microbes in the body. Infections at this site can cause significant perturbations in the microbiota, known as dysbiosis, that facilitate the expansion of pathobionts, and can elicit inappropriate immune responses that impair the intestinal barrier function. Dysbiosis typically occurs during intestinal infection with Toxoplasma gondii . Host resistance to T. gondii depends on a potent Th1 response. In addition, a Th17 response is also elicited. How Th17 cells contribute to the host response to T. gondii remains unclear. Here we show that class I-restricted T cell-associated molecule (CRTAM) expression on T cells is required for an optimal IL-17 production during T. gondii infection. Moreover, that the lack of IL-17, results in increased immunopathology caused by an impaired antimicrobial peptide production and bacterial translocation from the intestinal lumen to the mesenteric lymph nodes and spleen.
- Published
- 2019
- Full Text
- View/download PDF
40. The Tumor Necrosis Factor Superfamily Member RANKL Suppresses Effector Cytokine Production in Group 3 Innate Lymphoid Cells.
- Author
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Bando JK, Gilfillan S, Song C, McDonald KG, Huang SC, Newberry RD, Kobayashi Y, Allan DSJ, Carlyle JR, Cella M, and Colonna M
- Subjects
- Animals, Cytokines biosynthesis, Cytokines immunology, Lymphocyte Subsets metabolism, Mice, Nuclear Receptor Subfamily 1, Group F, Member 3 biosynthesis, Nuclear Receptor Subfamily 1, Group F, Member 3 immunology, RANK Ligand metabolism, Receptors, CCR6 immunology, Immunity, Innate immunology, Lymphocyte Subsets immunology, RANK Ligand immunology
- Abstract
While signals that activate group 3 innate lymphoid cells (ILC3s) have been described, the factors that negatively regulate these cells are less well understood. Here we found that the tumor necrosis factor (TNF) superfamily member receptor activator of nuclear factor κB ligand (RANKL) suppressed ILC3 activity in the intestine. Deletion of RANKL in ILC3s and T cells increased C-C motif chemokine receptor 6 (CCR6)
+ ILC3 abundance and enhanced production of interleukin-17A (IL-17A) and IL-22 in response to IL-23 and during infection with the enteric murine pathogen Citrobacter rodentium. Additionally, CCR6+ ILC3s produced higher amounts of the master transcriptional regulator RORγt at steady state in the absence of RANKL. RANKL-mediated suppression was independent of T cells, and instead occurred via interactions between CCR6+ ILC3s that expressed both RANKL and its receptor, RANK. Thus, RANK-RANKL interactions between ILC3s regulate ILC3 abundance and activation, suggesting that cell clustering may control ILC3 activity., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
41. Modulation of gene transcription and epigenetics of colon carcinoma cells by bacterial membrane vesicles.
- Author
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Vdovikova S, Gilfillan S, Wang S, Dongre M, Wai SN, and Hurtado A
- Subjects
- Cell Line, Colonic Neoplasms genetics, Humans, Cell Membrane metabolism, Colonic Neoplasms microbiology, Colonic Neoplasms pathology, Epigenesis, Genetic, Escherichia coli K12 cytology, Transcription, Genetic, Vibrio cholerae cytology
- Abstract
Interactions between bacteria and colon cancer cells influence the transcription of the host cell. Yet is it undetermined whether the bacteria itself or the communication between the host and bacteria is responsible for the genomic changes in the eukaryotic cell. Now, we have investigated the genomic and epigenetic consequences of co-culturing colorectal carcinoma cells with membrane vesicles from pathogenic bacteria Vibrio cholerae and non-pathogenic commensal bacteria Escherichia coli. Our study reveals that membrane vesicles from pathogenic and commensal bacteria have a global impact on the gene expression of colon-carcinoma cells. The changes in gene expression correlate positively with both epigenetic changes and chromatin accessibility of promoters at transcription start sites of genes induced by both types of membrane vesicles. Moreover, we have demonstrated that membrane vesicles obtained only from V. cholerae induced the expression of genes associated with epithelial cell differentiation. Altogether, our study suggests that the observed genomic changes in host cells might be due to specific components of membrane vesicles and do not require communication by direct contact with the bacteria.
- Published
- 2018
- Full Text
- View/download PDF
42. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism.
- Author
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Song WM, Joshita S, Zhou Y, Ulland TK, Gilfillan S, and Colonna M
- Subjects
- ADAM17 Protein metabolism, Animals, Brain pathology, Cell Count, Gliosis genetics, Gliosis pathology, Humans, Membrane Glycoproteins metabolism, Mice, Transgenic, Myeloid Cells metabolism, Myeloid Cells pathology, Neurons metabolism, Receptors, Immunologic metabolism, Solubility, Membrane Glycoproteins genetics, Microglia metabolism, Polymorphism, Single Nucleotide genetics, Receptors, Immunologic genetics
- Abstract
Alzheimer's disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown. We generated transgenic mice expressing human CV or R47H TREM2 and lacking endogenous TREM2 in the 5XFAD AD model. Only the CV transgene restored amyloid-β-induced microgliosis and microglial activation, indicating that R47H impairs TREM2 function in vivo. Remarkably, soluble TREM2 was found on neurons and plaques in CV- but not R47H-expressing 5XFAD brains, although in vitro CV and R47H were shed similarly via Adam17 proteolytic activity. These results demonstrate that TREM2 interacts with neurons and plaques duing amyloid-β accumulation and R47H impairs this interaction., (© 2018 Song et al.)
- Published
- 2018
- Full Text
- View/download PDF
43. HIV and mental illness in Malawi and the neuropsychiatric sequelae of efavirenz.
- Author
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Drury A, Gleadow-Ware S, Gilfillan S, and Ahrens J
- Subjects
- Adult, Alkynes, Benzoxazines adverse effects, Cyclopropanes, Female, HIV Infections psychology, Humans, Male, Mental Disorders psychology, Anti-HIV Agents adverse effects, Anti-HIV Agents therapeutic use, Benzoxazines therapeutic use, HIV Infections drug therapy, Mental Disorders chemically induced
- Abstract
Introduction: Little is published about mental disorders in Malawi, specifically in relation to Human Immunodeficiency Virus (HIV) and it's treatment. Efavirenz is a medication commonly used as part of triple therapy for HIV treatment. Indeed, in 2013, Malawi introduced 5A with Efavirenz as part of it's 1st line treatment for HIV. There exists some literature documenting known psychiatric side effects of Efavirenz, which include anxiety, mood changes, nightmares, psychosis and suicidal ideation. Little is known about what features are most common in the presentation and what factors in the patient and drug which may make this reaction more likely., Aim: The aim of this commentary is to review the association between HIV and psychiatric disorder, and consider the neuropsychiatric side-effects of Efavirenz., Method: An evaluative literature review was completed by means of multiple electronic database search as well as an additional manual search to obtain published works identified through the electronic search. Search terms used were: Efavirenz, Acquired Immunodeficiency Syndrome, Africa, Antiretroviral Therapy, Developing Countries, Malawi, Mental Disorders, Public Health, and Psychiatry., Conclusion: This is an important area of study, as potentially large numbers of individuals with HIV are being placed on Efavirenz as first line treatment, yet 60% may experience some form of neuropsychiatric side effects.
- Published
- 2018
- Full Text
- View/download PDF
44. Jak3 deficiency blocks innate lymphoid cell development.
- Author
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Robinette ML, Cella M, Telliez JB, Ulland TK, Barrow AD, Capuder K, Gilfillan S, Lin LL, Notarangelo LD, and Colonna M
- Subjects
- Animals, Cell Differentiation genetics, Cell Proliferation genetics, Cells, Cultured, Humans, Immunity, Innate, Interferon-gamma metabolism, Janus Kinase 3 antagonists & inhibitors, Mice, Mice, Mutant Strains, Phenotype, Piperidines pharmacology, Pyrimidines pharmacology, Pyrroles pharmacology, Arthritis, Rheumatoid drug therapy, Bone Marrow Cells physiology, Janus Kinase 3 genetics, Killer Cells, Natural physiology, Mutation genetics, Piperidines therapeutic use, Pyrimidines therapeutic use, Pyrroles therapeutic use, Severe Combined Immunodeficiency genetics
- Abstract
Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1
tm1Ven /LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3, generating a SCID phenotype and an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs). Mechanistically, Jak3 deficiency blocks ILC differentiation in the bone marrow at the ILC precursor and the pre-NK cell progenitor. We further demonstrate that the pan-JAK inhibitor tofacitinib and the specific JAK3 inhibitor PF-06651600 impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ, without affecting ILC3 production of IL-22. Both inhibitors impaired the proliferation of iILC1 and ILC3 and differentiation of human ILC in vitro. Tofacitinib is currently approved for the treatment of moderate-to-severely active rheumatoid arthritis. Both tofacitinib and PF-06651600 are currently in clinical trials for several other immune-mediated conditions. Our data suggest that therapeutic inhibition of JAK may also impact ILCs and, to some extent, underlie clinical efficacy.- Published
- 2018
- Full Text
- View/download PDF
45. TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.
- Author
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Ulland TK, Song WM, Huang SC, Ulrich JD, Sergushichev A, Beatty WL, Loboda AA, Zhou Y, Cairns NJ, Kambal A, Loginicheva E, Gilfillan S, Cella M, Virgin HW, Unanue ER, Wang Y, Artyomov MN, Holtzman DM, and Colonna M
- Subjects
- AMP-Activated Protein Kinases metabolism, Alzheimer Disease metabolism, Animals, Autophagy, Creatinine analogs & derivatives, Creatinine metabolism, Disease Models, Animal, Humans, Lectins, C-Type metabolism, Macrophages metabolism, Membrane Glycoproteins genetics, Mice, Microglia pathology, Neurites metabolism, Plaque, Amyloid metabolism, Receptors, Immunologic genetics, TOR Serine-Threonine Kinases metabolism, Alzheimer Disease pathology, Energy Metabolism, Membrane Glycoproteins metabolism, Microglia metabolism, Receptors, Immunologic metabolism
- Abstract
Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
46. Microbiota induces tonic CCL2 systemic levels that control pDC trafficking in steady state.
- Author
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Swiecki M, Miller HL, Sesti-Costa R, Cella M, Gilfillan S, and Colonna M
- Subjects
- Animals, Apoptosis, Cells, Cultured, Cytokines metabolism, Homeostasis, Inflammation microbiology, Inflammation Mediators metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mononuclear Phagocyte System, Receptors, CCR2 genetics, Receptors, CCR2 metabolism, Specific Pathogen-Free Organisms, Cell Movement, Chemokine CCL2 metabolism, Dendritic Cells immunology, Inflammation immunology, Microbiota immunology
- Abstract
Plasmacytoid dendritic cells (pDCs) detect viruses initiating antiviral type I interferon responses. The microbiota is known to shape immune responses, but whether it influences pDC homeostasis and/or function is poorly understood. By comparing pDCs in germ-free and specific pathogen-free mice, we found that the microbiota supports homeostatic trafficking by eliciting constitutive levels of the chemokine CCL2 that engages CCR2. Mononuclear phagocytes were required for tonic CCL2 levels. CCL2 was particularly important for trafficking of a CCR2
hi subset of pDCs that produced proinflammatory cytokines and was prone to apoptosis. We further demonstrated that CCR2 was also essential for pDC migration during inflammation. Wild-type (WT):Ccr2-/- mixed bone marrow chimeras revealed that CCR2 promotes pDC migration in a cell-intrinsic manner. Overall, we identify a novel role for the microbiota in shaping immunity, which includes induction of CCL2 levels that control homeostatic trafficking of pDCs.- Published
- 2017
- Full Text
- View/download PDF
47. Expression of CD226 is associated to but not required for NK cell education.
- Author
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Wagner AK, Kadri N, Snäll J, Brodin P, Gilfillan S, Colonna M, Bernhardt G, Höglund P, Kärre K, and Chambers BJ
- Subjects
- Animals, Antigens, Differentiation, T-Lymphocyte genetics, Cells, Cultured, Female, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I immunology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NK Cell Lectin-Like Receptor Subfamily C genetics, NK Cell Lectin-Like Receptor Subfamily C immunology, Nectins metabolism, Neoplasms immunology, Receptors, Virus metabolism, beta 2-Microglobulin genetics, Antigens, Differentiation, T-Lymphocyte biosynthesis, Antigens, Differentiation, T-Lymphocyte immunology, Killer Cells, Natural immunology, Lymphocyte Activation immunology
- Abstract
DNAX accessory molecule-1 (DNAM-1, also known as CD226) is an activating receptor expressed on subsets of natural killer (NK) and T cells, interacts with its ligands CD155 or CD112, and has co-varied expression with inhibitory receptors. Since inhibitory receptors control NK-cell activation and are necessary for MHC-I-dependent education, we investigated whether DNAM-1 expression is also involved in NK-cell education. Here we show an MHC-I-dependent correlation between DNAM-1 expression and NK-cell education, and an association between DNAM-1 and NKG2A that occurs even in MHC class I deficient mice. DNAM-1 is expressed early during NK-cell development, precedes the expression of MHC-I-specific inhibitory receptors, and is modulated in an education-dependent fashion. Cd226
-/- mice have missing self-responses and NK cells with a normal receptor repertoire. We propose a model in which NK-cell education prevents or delays downregulation of DNAM-1. This molecule endows educated NK cells with enhanced effector functions but is dispensable for education.- Published
- 2017
- Full Text
- View/download PDF
48. IL-15 sustains IL-7R-independent ILC2 and ILC3 development.
- Author
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Robinette ML, Bando JK, Song W, Ulland TK, Gilfillan S, and Colonna M
- Subjects
- Animals, Female, Immunity, Innate, Interleukin-15 genetics, Intestine, Small immunology, Killer Cells, Natural immunology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mucous Membrane immunology, Receptors, Interleukin-7 genetics, Signal Transduction, Interleukin-15 immunology, Lymphocyte Subsets immunology, Lymphocytes immunology, Receptors, Interleukin-7 immunology
- Abstract
The signals that maintain tissue-resident innate lymphoid cells (ILC) in different microenvironments are incompletely understood. Here we show that IL-7 receptor (IL-7R) is not strictly required for the development of any ILC subset, as residual cells persist in the small intestinal lamina propria (siLP) of adult and neonatal Il7ra
-/- mice. Il7ra-/- ILC2 primarily express an ST2- phenotype, but are not inflammatory ILC2. CCR6+ ILC3, which express higher Bcl-2 than other ILC3, are the most abundant subset in Il7ra-/- siLP. All ILC subsets are functionally competent in vitro, and are sufficient to provide enhanced protection to infection with C. rodentium. IL-15 equally sustains wild-type and Il7ra-/- ILC survival in vitro and compensates for IL-7R deficiency, as residual ILCs are depleted in mice lacking both molecules. Collectively, these data demonstrate that siLP ILCs are not completely IL-7R dependent, but can persist partially through IL-15 signalling.- Published
- 2017
- Full Text
- View/download PDF
49. CTCF modulates Estrogen Receptor function through specific chromatin and nuclear matrix interactions.
- Author
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Fiorito E, Sharma Y, Gilfillan S, Wang S, Singh SK, Satheesh SV, Katika MR, Urbanucci A, Thiede B, Mills IG, and Hurtado A
- Subjects
- Binding Sites, CCCTC-Binding Factor, Enhancer Elements, Genetic, Estrogens physiology, Humans, MCF-7 Cells, Protein Binding, Transcriptional Activation, Cell Nucleus metabolism, Chromatin metabolism, Receptors, Estrogen metabolism, Repressor Proteins physiology
- Abstract
Enhancer regions and transcription start sites of estrogen-target regulated genes are connected by means of Estrogen Receptor long-range chromatin interactions. Yet, the complete molecular mechanisms controlling the transcriptional output of engaged enhancers and subsequent activation of coding genes remain elusive. Here, we report that CTCF binding to enhancer RNAs is enriched when breast cancer cells are stimulated with estrogen. CTCF binding to enhancer regions results in modulation of estrogen-induced gene transcription by preventing Estrogen Receptor chromatin binding and by hindering the formation of additional enhancer-promoter ER looping. Furthermore, the depletion of CTCF facilitates the expression of target genes associated with cell division and increases the rate of breast cancer cell proliferation. We have also uncovered a genomic network connecting loci enriched in cell cycle regulator genes to nuclear lamina that mediates the CTCF function. The nuclear lamina and chromatin interactions are regulated by estrogen-ER. We have observed that the chromatin loops formed when cells are treated with estrogen establish contacts with the nuclear lamina. Once there, the portion of CTCF associated with the nuclear lamina interacts with enhancer regions, limiting the formation of ER loops and the induction of genes present in the loop. Collectively, our results reveal an important, unanticipated interplay between CTCF and nuclear lamina to control the transcription of ER target genes, which has great implications in the rate of growth of breast cancer cells., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2016
- Full Text
- View/download PDF
50. MHC II+ resident peritoneal and pleural macrophages rely on IRF4 for development from circulating monocytes.
- Author
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Kim KW, Williams JW, Wang YT, Ivanov S, Gilfillan S, Colonna M, Virgin HW, Gautier EL, and Randolph GJ
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Antigens, Differentiation, T-Lymphocyte metabolism, Cell Differentiation drug effects, Macrophages, Peritoneal drug effects, Mice, Mice, Inbred C57BL, Monocytes drug effects, Monocytes metabolism, Receptors, CCR2 metabolism, Genes, MHC Class II, Interferon Regulatory Factors metabolism, Macrophages, Peritoneal metabolism, Monocytes cytology, Pleura cytology
- Abstract
Peritoneal and pleural resident macrophages in the mouse share common features and in each compartment exist as two distinct subpopulations: F4/80(+) macrophages and MHC II(+) CD11c(+) macrophages. F4/80(+) macrophages derive from embryonic precursors, and their maintenance is controlled by Gata6. However, the origin and regulatory factors that maintain MHC II(+) macrophages remain unknown. Here, we show that the MHC II(+) macrophages arise postnatally from CCR2-dependent precursors that resemble monocytes. Monocytes continuously replenish this subset through adulthood. Gene expression analysis identified distinct surface markers like CD226 and revealed that the transcription factor IRF4 was selectively expressed in these macrophages relative to other organs. Monocytes first entered peritoneal or pleural cavities to become MHC II(+) cells that up-regulated CD226 and CD11c later as they continued to mature. In the absence of IRF4 or after administration of oral antibiotics, MHC II(+)CD226(-)CD11c(-) monocyte-derived cells accumulated in peritoneal and pleural cavities, but CD11c(+) CD226(+) macrophages were lost. Thus, MHC II(+) resident peritoneal and pleural macrophages are continuously replenished by blood monocytes recruited to the peritoneal and pleural cavities constitutively, starting after birth, where they require IRF4 and signals likely derived from the microbiome to fully differentiate., (© 2016 Kim et al.)
- Published
- 2016
- Full Text
- View/download PDF
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