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173 results on '"Healy, Luke M."'

1. An adapted protocol to derive microglia from stem cells and its application in the study of CSF1R-related disorders

Author

Dorion, Marie-France, Casas, Diana, Shlaifer, Irina, Yaqubi, Moein, Fleming, Peter, Karpilovsky, Nathan, Chen, Carol X.-Q., Nicouleau, Michael, Piscopo, Valerio E. C., MacDougall, Emma J., Alluli, Aeshah, Goldsmith, Taylor M., Schneider, Alexandria, Dorion, Samuel, Aprahamian, Nathalia, MacDonald, Adam, Thomas, Rhalena A., Dudley, Roy W. R., Hall, Jeffrey A., Fon, Edward A., Antel, Jack P., Stratton, Jo Anne, Durcan, Thomas M., La Piana, Roberta, and Healy, Luke M.

Published
2024
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3. Development of a Chimeric Model to Study and Manipulate Human Microglia In Vivo

Author

Hasselmann, Jonathan, Coburn, Morgan A, England, Whitney, Figueroa Velez, Dario X, Kiani Shabestari, Sepideh, Tu, Christina H, McQuade, Amanda, Kolahdouzan, Mahshad, Echeverria, Karla, Claes, Christel, Nakayama, Taylor, Azevedo, Ricardo, Coufal, Nicole G, Han, Claudia Z, Cummings, Brian J, Davtyan, Hayk, Glass, Christopher K, Healy, Luke M, Gandhi, Sunil P, Spitale, Robert C, and Blurton-Jones, Mathew

Subjects
Genetics, Stem Cell Research, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Alzheimer Disease, Amyloid beta-Peptides, Animals, Brain, Cell Differentiation, Disease Models, Animal, Gene Expression, Granulocyte-Macrophage Colony-Stimulating Factor, Hematopoietic Stem Cell Transplantation, Humans, Induced Pluripotent Stem Cells, Macrophage Colony-Stimulating Factor, Mice, Mice, Transgenic, Microglia, Plaque, Amyloid, Thrombopoietin, Transplantation Chimera, Alzheimer’s disease, TREM-2, beta-amyloid, chimera, hematopoietic, humanized, microglia, neurodegeneration, pluripotent, stem cells, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

iPSC-derived microglia offer a powerful tool to study microglial homeostasis and disease-associated inflammatory responses. Yet, microglia are highly sensitive to their environment, exhibiting transcriptomic deficiencies when kept in isolation from the brain. Furthermore, species-specific genetic variations demonstrate that rodent microglia fail to fully recapitulate the human condition. To address this, we developed an approach to study human microglia within a surrogate brain environment. Transplantation of iPSC-derived hematopoietic-progenitors into the postnatal brain of humanized, immune-deficient mice results in context-dependent differentiation into microglia and other CNS macrophages, acquisition of an ex vivo human microglial gene signature, and responsiveness to both acute and chronic insults. Most notably, transplanted microglia exhibit robust transcriptional responses to Aβ-plaques that only partially overlap with that of murine microglia, revealing new, human-specific Aβ-responsive genes. We therefore have demonstrated that this chimeric model provides a powerful new system to examine the in vivo function of patient-derived and genetically modified microglia.

Published
2019

5. Single-cell RNA sequencing reveals time- and sex-specific responses of mouse spinal cord microglia to peripheral nerve injury and links ApoE to chronic pain

Author

Tansley, Shannon, Uttam, Sonali, Ureña Guzmán, Alba, Yaqubi, Moein, Pacis, Alain, Parisien, Marc, Deamond, Haley, Wong, Calvin, Rabau, Oded, Brown, Nicole, Haglund, Lisbet, Ouellet, Jean, Santaguida, Carlo, Ribeiro-da-Silva, Alfredo, Tahmasebi, Soroush, Prager-Khoutorsky, Masha, Ragoussis, Jiannis, Zhang, Ji, Salter, Michael W., Diatchenko, Luda, Healy, Luke M., Mogil, Jeffrey S., and Khoutorsky, Arkady

Published
2022
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7. iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases

Author

Abud, Edsel M, Ramirez, Ricardo N, Martinez, Eric S, Healy, Luke M, Nguyen, Cecilia HH, Newman, Sean A, Yeromin, Andriy V, Scarfone, Vanessa M, Marsh, Samuel E, Fimbres, Cristhian, Caraway, Chad A, Fote, Gianna M, Madany, Abdullah M, Agrawal, Anshu, Kayed, Rakez, Gylys, Karen H, Cahalan, Michael D, Cummings, Brian J, Antel, Jack P, Mortazavi, Ali, Carson, Monica J, Poon, Wayne W, and Blurton-Jones, Mathew

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Stem Cell Research - Induced Pluripotent Stem Cell - Human, Neurodegenerative, Aging, Genetics, Brain Disorders, Stem Cell Research, Dementia, Stem Cell Research - Induced Pluripotent Stem Cell, Alzheimer's Disease, Acquired Cognitive Impairment, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Brain, Cells, Cultured, Cytokines, Disease Models, Animal, Humans, Induced Pluripotent Stem Cells, Mice, Microglia, Peptide Fragments, 3D organoids, AD-GWAS, Alzheimer’s disease, Beta-amyloid, Tau, cell models of disease, induced pluripotent stem cells, microglia, mouse transplantation, neurodegenerative diseases, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. iMGLs were used to examine the effects of Aβ fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease.

Published
2017

11. MerTK is a mediator of alpha-synuclein fibril uptake by human microglia.

Author

Dorion, Marie-France, Yaqubi, Moein, Senkevich, Konstantin, Kieran, Nicholas W, MacDonald, Adam, Chen, Carol X Q, Luo, Wen, Wallis, Amber, Shlaifer, Irina, Hall, Jeffery A, Dudley, Roy W R, Glass, Ian A, Laboratory, Birth Defects Research, Stratton, Jo Anne, Fon, Edward A, Bartels, Tim, Antel, Jack P, Gan-or, Ziv, Durcan, Thomas M, and Healy, Luke M

Subjects
LEWY body dementia, ALPHA-synuclein, MICROGLIA, PARKINSON'S disease, PROTEIN-tyrosine kinases
Abstract

Mer tyrosine kinase (MerTK) is a receptor tyrosine kinase that mediates non-inflammatory, homeostatic phagocytosis of diverse types of cellular debris. Highly expressed on the surface of microglial cells, MerTK is of importance in brain development, homeostasis, plasticity and disease. Yet, involvement of this receptor in the clearance of protein aggregates that accumulate with ageing and in neurodegenerative diseases has yet to be defined. The current study explored the function of MerTK in the microglial uptake of alpha-synuclein fibrils which play a causative role in the pathobiology of synucleinopathies. Using human primary and induced pluripotent stem cell-derived microglia, the MerTK-dependence of alpha-synuclein fibril internalization was investigated in vitro. Relevance of this pathway in synucleinopathies was assessed through burden analysis of MERTK variants and analysis of MerTK expression in patient-derived cells and tissues. Pharmacological inhibition of MerTK and siRNA-mediated MERTK knockdown both caused a decreased rate of alpha-synuclein fibril internalization by human microglia. Consistent with the non-inflammatory nature of MerTK-mediated phagocytosis, alpha-synuclein fibril internalization was not observed to induce secretion of pro-inflammatory cytokines such as IL-6 or TNF, and downmodulated IL-1β secretion from microglia. Burden analysis in two independent patient cohorts revealed a significant association between rare functionally deleterious MERTK variants and Parkinson's disease in one of the cohorts (P = 0.002). Despite a small upregulation in MERTK mRNA expression in nigral microglia from Parkinson's disease/Lewy body dementia patients compared to those from non-neurological control donors in a single-nuclei RNA-sequencing dataset (P = 5.08 × 10−21), no significant upregulation in MerTK protein expression was observed in human cortex and substantia nigra lysates from Lewy body dementia patients compared to controls. Taken together, our findings define a novel role for MerTK in mediating the uptake of alpha-synuclein fibrils by human microglia, with possible involvement in limiting alpha-synuclein spread in synucleinopathies such as Parkinson's disease. Upregulation of this pathway in synucleinopathies could have therapeutic values in enhancing alpha-synuclein fibril clearance in the brain. [ABSTRACT FROM AUTHOR]

Published
2024
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16. Analysis of the microglia transcriptome across the human lifespan using single cell RNA sequencing.

Author

Yaqubi, Moein, Groh, Adam M. R., Dorion, Marie-France, Afanasiev, Elia, Luo, Julia Xiao Xuan, Hashemi, Hadi, Sinha, Sarthak, Kieran, Nicholas W., Blain, Manon, Cui, Qiao-Ling, Biernaskie, Jeff, Srour, Myriam, Dudley, Roy, Hall, Jeffery A., Sonnen, Joshua A., Arbour, Nathalie, Prat, Alexandre, Stratton, Jo Anne, Antel, Jack, and Healy, Luke M.

Subjects
RNA sequencing, MICROGLIA, CENTRAL nervous system, TRANSCRIPTOMES
Abstract

Background: Microglia are tissue resident macrophages with a wide range of critically important functions in central nervous system development and homeostasis. Method: In this study, we aimed to characterize the transcriptional landscape of ex vivo human microglia across different developmental ages using cells derived from pre-natal, pediatric, adolescent, and adult brain samples. We further confirmed our transcriptional observations using ELISA and RNAscope. Results: We showed that pre-natal microglia have a distinct transcriptional and regulatory signature relative to their post-natal counterparts that includes an upregulation of phagocytic pathways. We confirmed upregulation of CD36, a positive regulator of phagocytosis, in pre-natal samples compared to adult samples in situ. Moreover, we showed adult microglia have more pro-inflammatory signature compared to microglia from other developmental ages. We indicated that adult microglia are more immune responsive by secreting increased levels of pro-inflammatory cytokines in response to LPS treatment compared to the pre-natal microglia. We further validated in situ up-regulation of IL18 and CXCR4 in human adult brain section compared to the pre-natal brain section. Finally, trajectory analysis indicated that the transcriptional signatures adopted by microglia throughout development are in response to a changing brain microenvironment and do not reflect predetermined developmental states. Conclusion: In all, this study provides unique insight into the development of human microglia and a useful reference for understanding microglial contribution to developmental and age-related human disease. [ABSTRACT FROM AUTHOR]

Published
2023
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18. Regional and age‐related diversity of human mature oligodendrocytes

Author

Yaqubi, Moein, primary, Luo, Julia Xiao Xuan, additional, Baig, Salma, additional, Cui, Qiao‐Ling, additional, Petrecca, Kevin, additional, Desu, Haritha, additional, Larochelle, Catherine, additional, Afanasiev, Elia, additional, Hall, Jeffery A., additional, Dudley, Roy, additional, Srour, Myriam, additional, Haglund, Lisbet, additional, Ouellet, Jean, additional, Georgiopoulos, Miltiadis, additional, Santaguida, Carlo, additional, Sonnen, Joshua A., additional, Healy, Luke M., additional, Stratton, Jo Anne, additional, Kennedy, Timothy E., additional, and Antel, Jack P., additional

Published
2022
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19. Additional file 3 of MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes

Author

Kieran, Nicholas W., Suresh, Rahul, Dorion, Marie-France, MacDonald, Adam, Blain, Manon, Wen, Dingke, Fuh, Shih-Chieh, Ryan, Fari, Diaz, Roberto J., Stratton, Jo Anne, Ludwin, Samuel K., Sonnen, Joshua A., Antel, Jack, and Healy, Luke M.

Abstract

Additional file 3: Figure S2. Primary human fetal astrocytes respond to in vitro stresses, and mice upregulate miR-210 around ischemic lesions. (A) Primary human astrocytes, oligodendrocytes, and microglia were separately cultured and analyzed for expression of canonically expressed genes of glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and ionized calcium binding adaptor molecule 1 (IBA1) by RT-qPCR. n = 3���4. (B) Primary human fetal astrocytes were immunostained with anti-GFAP, anti-O4, and anti-PU.1 antibodies. A CX7 automated microscope was used to quantify the percent positive astrocytes for each marker, n = 4. (C) Primary human astrocytes were treated in inflammatory (���I���) metabolic (���M���) or hypoxic (���H���) stress conditions induced by IL1b, glucose-free media, or a 1% oxygen chamber for 24 h compared to untreated control. RT-qPCR assessment of CXCL10, HMOX1, and MCT4 expression was measured to confirm the astrocytic response to inflammatory, metabolic, and hypoxic stress conditions, respectively, n = 4���6. (D) HeLa cells were left in normoxic (���N���) conditions for 48 h or were treated in 1% O2 (hypoxia, H) for the noted time. After 2���48 h, the cells were removed and were immediately lysed with RIPA buffer for subsequent Western blot. n = 3. (E) Graphical representation of the area investigated for miR-210 expression using miRscope. miR-210 was quantified in the highlighted region around the infarct site (left), and in the respectively highlighted region on the contralateral side of the brain (right). 300���500 cells were counted per brain section. (F) Representative images and quantification of microRNAscope (miRscope) of miR-210 around MCAO lesions (labeled as infarct) or on the contralateral side of the brain (labeled as control). Scale bar = 20 ��m. Quantification was performed by manual counting of the number of nuclei positive for one or more red puncta. Red dots show miR-210 expression, and DAPI (blue) was used as a counterstain. Each dot in image F represents a separate tissue section all derived from one mouse, resulting in five sections imaged per brain region.

Published
2022
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20. Additional file 4 of MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes

Author

Kieran, Nicholas W., Suresh, Rahul, Dorion, Marie-France, MacDonald, Adam, Blain, Manon, Wen, Dingke, Fuh, Shih-Chieh, Ryan, Fari, Diaz, Roberto J., Stratton, Jo Anne, Ludwin, Samuel K., Sonnen, Joshua A., Antel, Jack, and Healy, Luke M.

Abstract

Additional file 4: Figure S3. microRNAs are differentially expressed in primary human astrocytes undergoing different stresses. (A) Primary human astrocytes, oligodendrocytes, and microglia were separately cultured and analyzed for expression of canonically expressed genes of glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and ionized calcium binding adaptor molecule 1 (IBA1) by RT-qPCR. n = 3���4. (B) Primary human fetal astrocytes were immunostained with anti-GFAP, anti-O4, and anti-PU.1 antibodies. A CX7 automated microscope was used to quantify the percent positive astrocytes for each marker, n = 4. (C) Primary human astrocytes were treated in inflammatory (���I���) metabolic (���M���) or hypoxic (���H���) stress conditions induced by IL1b, glucose-free media, or a 1% oxygen chamber for 24 h compared to untreated control. RT-qPCR assessment of CXCL10, HMOX1, and MCT4 expression was measured to confirm the astrocytic response to inflammatory, metabolic, and hypoxic stress conditions, respectively, n = 4���6. (D) HeLa cells were left in normoxic (���N���) conditions for 48 h or were treated in 1% O2 (hypoxia, H) for the noted time period. After 2���48 h, the cells were removed and were immediately lysed with RIPA buffer for subsequent Western blot. n = 3.

Published
2022
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21. Additional file 5 of MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes

Author

Kieran, Nicholas W., Suresh, Rahul, Dorion, Marie-France, MacDonald, Adam, Blain, Manon, Wen, Dingke, Fuh, Shih-Chieh, Ryan, Fari, Diaz, Roberto J., Stratton, Jo Anne, Ludwin, Samuel K., Sonnen, Joshua A., Antel, Jack, and Healy, Luke M.

Abstract

Additional file 5: Figure S4. Astrocytic Metabolism and MCT4 Protein Expression is unchanged after 24- and 48-h 210M transfection, respectively. (A) Oxygen Consumption Rate (OCR) was measured in primary human astrocytes 24-h after transfection of 210S or 210M. n = 4 with 10 technical replicates for OCR experiments. (B) Extracellular Acidification Rate (ECAR) was measured in primary human astrocytes 24-h after transfection of 210S or 210M. n = 4 with 20 technical replicates for ECAR experiments. (C) Protein expression of MCT4 and Beta Tubulin (Beta-Tub) were measured by western blot in six separate human samples. Data is graphed as the fold change of MCT4 expression normalized to Beta-Tubulin expression and relative to the expression of 210S. For (C), each dot represents a separate human sample. (D) RT-qPCR assessment of LDHA in 210M-transfected cells relative to 210S-transfected cells 48 h after transfection. Mean �� SEM of 6 donors. Two-way ANOVA with Sidak���s correction was performed for Seahorse experiments, whereas t-test was used for MCT4 and LDHA expression. *p

Published
2022
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22. Additional file 6 of MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes

Author

Kieran, Nicholas W., Suresh, Rahul, Dorion, Marie-France, MacDonald, Adam, Blain, Manon, Wen, Dingke, Fuh, Shih-Chieh, Ryan, Fari, Diaz, Roberto J., Stratton, Jo Anne, Ludwin, Samuel K., Sonnen, Joshua A., Antel, Jack, and Healy, Luke M.

Abstract

Additional file 6: Figure S5. 210M does not affect astrocytic expression of select pro- or anti-inflammatory genes. Select genes that have previously been identified to promote or antagonize inflammation in astrocytes were measured by RT-qPCR in primary human fetal astrocytes. Cells were transfected with 210S or 210M and left otherwise untreated or treated with hypoxia (H) and inflammation (I) using 1% oxygen and IL1b, respectively. n = 3���4, data is graphed as mean �� SEM and was analyzed using one-way ANOVA with Sidak���s multiple comparison test.

Published
2022
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23. Additional file 1 of MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes

Author

Kieran, Nicholas W., Suresh, Rahul, Dorion, Marie-France, MacDonald, Adam, Blain, Manon, Wen, Dingke, Fuh, Shih-Chieh, Ryan, Fari, Diaz, Roberto J., Stratton, Jo Anne, Ludwin, Samuel K., Sonnen, Joshua A., Antel, Jack, and Healy, Luke M.

Abstract

Additional file 1: Table S1. Mean cycle threshold values of microRNAs from white matter and gray matter astrocytes.

Published
2022
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24. Human Oligodendrocyte Myelination Potential; Relation to Age and Differentiation

Author

Luo, Julia Xiao Xuan, primary, Cui, Qiao‐Ling, additional, Yaqubi, Moein, additional, Hall, Jeffery A., additional, Dudley, Roy, additional, Srour, Myriam, additional, Addour, Nassima, additional, Jamann, Hélène, additional, Larochelle, Catherine, additional, Blain, Manon, additional, Healy, Luke M., additional, Stratton, Jo Anne, additional, Sonnen, Joshua A., additional, Kennedy, Timothy E., additional, and Antel, Jack P., additional

Published
2022
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27. Pro-inflammatory adiponectin in pediatric-onset multiple sclerosis

Author

Nyirenda, Mukanthu H, primary, Fadda, Giulia, additional, Healy, Luke M, additional, Mexhitaj, Ina, additional, Poliquin-Lasnier, Laurence, additional, Hanwell, Heather, additional, Saveriano, Alexander W, additional, Rozenberg, Ayal, additional, Li, Rui, additional, Moore, Craig S, additional, Belabani, Chahrazed, additional, Johnson, Trina, additional, O’Mahony, Julia, additional, Arnold, Douglas L, additional, Yeh, E Ann, additional, Marrie, Ruth Ann, additional, Dunn, Shannon, additional, Banwell, Brenda, additional, and Bar-Or;, Amit, additional

Published
2021
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28. Single-cell RNA sequencing reveals time- and sex-specific responses of spinal cord microglia to peripheral nerve injury and links ApoE to neuropathic pain

Author

Tansley, Shannon, primary, Uttam, Sonali, additional, Ureña Guzmán, Alba, additional, Yaqubi, Moein, additional, Pacis, Alain, additional, Parisien, Marc, additional, Rabau, Oded, additional, Haglund, Lisbet, additional, Ouellet, Jean, additional, Santaguida, Carlo, additional, Ragoussis, Jiannis, additional, Zhang, Ji, additional, Salter, Michael W, additional, Diatchenko, Luda, additional, Healy, Luke M., additional, Mogil, Jeffrey S., additional, and Khoutorsky, Arkady, additional

Published
2020
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33. RIC3, the cholinergic anti-inflammatory pathway, and neuroinflammation

Author

Ben-David, Yael, primary, Kagan, Sara, additional, Cohen Ben-Ami, Hagit, additional, Rostami, Jinar, additional, Mizrahi, Tehila, additional, Kulkarni, Abhijit R., additional, Thakur, Ganesh A., additional, Vaknin-Dembinsky, Adi, additional, Healy, Luke M., additional, Brenner, Talma, additional, and Treinin, Millet, additional

Published
2020
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35. Implementation of an antibody characterization procedure and application to the major ALS/FTD disease gene C9ORF72

Author

Laflamme, Carl, primary, McKeever, Paul M, additional, Kumar, Rahul, additional, Schwartz, Julie, additional, Kolahdouzan, Mahshad, additional, Chen, Carol X, additional, You, Zhipeng, additional, Benaliouad, Faiza, additional, Gileadi, Opher, additional, McBride, Heidi M, additional, Durcan, Thomas M, additional, Edwards, Aled M, additional, Healy, Luke M, additional, Robertson, Janice, additional, and McPherson, Peter S, additional

Published
2019
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36. Author response: Implementation of an antibody characterization procedure and application to the major ALS/FTD disease gene C9ORF72

Author

Laflamme, Carl, primary, McKeever, Paul M, additional, Kumar, Rahul, additional, Schwartz, Julie, additional, Kolahdouzan, Mahshad, additional, Chen, Carol X, additional, You, Zhipeng, additional, Benaliouad, Faiza, additional, Gileadi, Opher, additional, McBride, Heidi M, additional, Durcan, Thomas M, additional, Edwards, Aled M, additional, Healy, Luke M, additional, Robertson, Janice, additional, and McPherson, Peter S, additional

Published
2019
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39. Cross-talk between Multiple Sclerosis (MS)-relevant B cell subsets and myeloid cells: potential contribution to the CNS-compartmentalized inflammation associated with disease progression (P2.2-083)

Author

Touil, Hanane, primary, Li, Rui, additional, Zuroff, Leah, additional, Moore, Craig, additional, Healy, Luke M., additional, Cignarella, Francesca, additional, Piccio, Laura, additional, Ludwin, Samuel, additional, Gommerman, Jennifer, additional, Prat, Alexandre, additional, Antel, Jack, additional, and Bar-Or, Amit, additional

Published
2019
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40. Distinct Function-Related Molecular Profile of Adult Human A2B5-Positive Pre-Oligodendrocytes Versus Mature Oligodendrocytes

Author

Esmonde-White, Caroline, primary, Yaqubi, Moein, additional, Bilodeau, Philippe A, additional, Cui, Qiao Ling, additional, Pernin, Florian, additional, Larochelle, Catherine, additional, Ghadiri, Mahtab, additional, Xu, Yu Kang T, additional, Kennedy, Timothy E, additional, Hall, Jeffery, additional, Healy, Luke M, additional, and Antel, Jack P, additional

Published
2019
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42. Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury

Author

Greenhalgh, Andrew D., primary, Zarruk, Juan G., additional, Healy, Luke M., additional, Baskar Jesudasan, Sam J., additional, Jhelum, Priya, additional, Salmon, Christopher K., additional, Formanek, Albert, additional, Russo, Matthew V., additional, Antel, Jack P., additional, McGavern, Dorian B., additional, McColl, Barry W., additional, and David, Samuel, additional

Published
2018
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45. Glioblastoma stem cell-derived exosomes induce M2 macrophages and PD-L1 expression on human monocytes

Author

Gabrusiewicz, Konrad, primary, Li, Xu, additional, Wei, Jun, additional, Hashimoto, Yuuri, additional, Marisetty, Anantha L., additional, Ott, Martina, additional, Wang, Fei, additional, Hawke, David, additional, Yu, John, additional, Healy, Luke M., additional, Hossain, Anwar, additional, Akers, Johnny C., additional, Maiti, Sourindra N., additional, Yamashita, Shinji, additional, Shimizu, Yuzaburo, additional, Dunner, Kenneth, additional, Zal, M. Anna, additional, Burks, Jared K., additional, Gumin, Joy, additional, Nwajei, Felix, additional, Rezavanian, Aras, additional, Zhou, Shouhao, additional, Rao, Ganesh, additional, Sawaya, Raymond, additional, Fuller, Gregory N., additional, Huse, Jason T., additional, Antel, Jack P., additional, Li, Shulin, additional, Cooper, Laurence, additional, Sulman, Erik P., additional, Chen, Clark, additional, Geula, Changiz, additional, Kalluri, Raghu, additional, Zal, Tomasz, additional, and Heimberger, Amy B., additional

Published
2018
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46. Divergent Neuroinflammatory Regulation of Microglial TREM Expression and Involvement of NF-κB

Author

Owens, Rosie, Grabert, Kathleen, Davies, Claire L., Alfieri, Alessio, Antel, Jack P., Healy, Luke M., and McColl, Barry W.

Subjects
Cellular and Molecular Neuroscience, myeloid cells, TREM2, Correction, microglia, microglial activation, NF-κB, lipopolysaccharide (LPS), Original Research, Neuroscience, neuroinflammation
Abstract

The triggering receptor expressed on myeloid cells (TREM) family of proteins are cell surface receptors with important roles in regulation of myeloid cell inflammatory activity. In the central nervous system, TREM2 is implicated in further roles in microglial homeostasis, neuroinflammation and neurodegeneration. Different TREM receptors appear to have contrasting roles in controlling myeloid immune activity therefore the relative and co-ordinated regulation of their expression is important to understand but is currently poorly understood. We sought to determine how microglial TREM expression is affected under neuroinflammatory conditions in vitro and in vivo. Our data show that microglial Trem1 and Trem2 gene expression are regulated in an opposing manner by lipopolysaccharide (LPS) in vitro in both adult murine and human microglia. LPS caused a significant induction of Trem1 and a contrasting suppression of Trem2 expression. We also observed similar divergent Trem1 and Trem2 responses in vivo in response to acute brain inflammation and acute cerebral ischaemia. Our data show that inhibition of NF-κB activation prevents the LPS-induced alterations in both Trem1 and Trem2 expression in vitro indicating NF-κB as a common signaling intermediate controlling these divergent responses. Distinct patterns of microglial Trem1 induction and Trem2 suppression to different Toll-like receptor (TLR) ligands were also evident, notably with Trem1 induction restricted to those ligands activating TLRs signaling via TRIF. Our data show co-ordinated but divergent regulation of microglial TREM receptor expression with a central role for NF-κB. Neuroinflammatory conditions that alter the balance in TREM expression could therefore be an important influence on microglial inflammatory and homeostatic activity with implications for neuroinflammatory and neurodegenerative disease.

Published
2016

50. Erratum: USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation

Author

Torre, Sabrina, primary, Polyak, Maria J, additional, Langlais, David, additional, Fodil, Nassima, additional, Kennedy, James M, additional, Radovanovic, Irena, additional, Berghout, Joanne, additional, Leiva-Torres, Gabriel A, additional, Krawczyk, Connie M, additional, Ilangumaran, Subburaj, additional, Mossman, Karen, additional, Liang, Chen, additional, Knobeloch, Klaus-Peter, additional, Healy, Luke M, additional, Antel, Jack, additional, Arbour, Nathalie, additional, Prat, Alexandre, additional, Majewski, Jacek, additional, Lathrop, Mark, additional, Vidal, Silvia M, additional, and Gros, Philippe, additional

Published
2016
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