186 results on '"Kubes, Paul"'
Search Results
2. Neutrophils during SARS‐CoV‐2 infection: Friend or foe?
- Author
-
Castanheira, Fernanda V. S. and Kubes, Paul
- Subjects
SARS-CoV-2 ,CORONAVIRUS diseases ,COVID-19 ,ADULT respiratory distress syndrome ,NEUTROPHILS - Abstract
Summary: Coronavirus disease 2019 (COVID‐19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and has resulted in more than 6 million deaths worldwide. COVID‐19 is a respiratory disease characterized by pulmonary dysfunction leading to acute respiratory distress syndrome (ARDs), as well as disseminated coagulation, and multi‐organ dysfunction. Neutrophils and neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of COVID‐19. In this review, we highlight key gaps in knowledge, discuss the heterogeneity of neutrophils during the evolution of the disease, how they can contribute to COVID‐19 pathogenesis, and potential therapeutic strategies that target neutrophil‐mediated inflammatory responses. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
3. A monocyte–leptin–angiogenesis pathway critical for repair post-infection.
- Author
-
Kratofil, Rachel M., Shim, Hanjoo B., Shim, Raymond, Lee, Woo Yong, Labit, Elodie, Sinha, Sarthak, Keenan, Catherine M., Surewaard, Bas G. J., Noh, Ji Yeon, Sun, Yuxiang, Sharkey, Keith A., Mack, Matthias, Biernaskie, Jeff, Deniset, Justin F., and Kubes, Paul
- Abstract
During infection, inflammatory monocytes are thought to be key for bacterial eradication, but this is hard to reconcile with the large numbers of neutrophils that are recruited for each monocyte that migrates to the afflicted tissue, and the much more robust microbicidal functions of the neutrophils. However, unlike neutrophils, monocytes have the capacity to convert to situationally specific macrophages that may have critical functions beyond infection control1,2. Here, using a foreign body coated with Staphylococcus aureus and imaging over time from cutaneous infection to wound resolution, we show that monocytes and neutrophils are recruited in similar numbers with low-dose infection but not with high-dose infection, and form a localization pattern in which monocytes surround the infection site, whereas neutrophils infiltrate it. Monocytes did not contribute to bacterial clearance but converted to macrophages that persisted for weeks after infection, regulating hypodermal adipocyte expansion and production of the adipokine hormone leptin. In infected monocyte-deficient mice there was increased persistent hypodermis thickening and an elevated leptin level, which drove overgrowth of dysfunctional blood vasculature and delayed healing, with a thickened scar. Ghrelin, which opposes leptin function3, was produced locally by monocytes, and reduced vascular overgrowth and improved healing post-infection. In sum, we find that monocytes function as a cellular rheostat by regulating leptin levels and revascularization during wound repair.Monocytes recruited to skin infection are not involved in bacterial clearance but instead regulate local angiogenesis and healing. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
4. Neutrophils in homeostasis and tissue repair.
- Author
-
Shim, Hanjoo Brian, Deniset, Justin F, and Kubes, Paul
- Subjects
NEUTROPHILS ,KILLER cells ,HOMEOSTASIS - Abstract
Neutrophils are the most abundant innate immune cell and are equipped with highly destructive molecular cargo. As such, these cells were long thought to be short-lived killer cells that unleash their full cytotoxic programs on pathogens following infection and on host bystander cells after sterile injury. However, this view of neutrophils is overly simplistic and as a result is outdated. Numerous studies now collectively highlight neutrophils as far more complex and having a host of homeostatic and tissue-reparative functions. In this review, we summarize these underappreciated roles across organs and injury models. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
5. Gata6+ resident peritoneal macrophages promote the growth of liver metastasis.
- Author
-
Hossain, Mokarram, Shim, Raymond, Lee, Woo-Yong, Sharpe, Arlene H., and Kubes, Paul
- Subjects
LIVER metastasis ,PROGRAMMED death-ligand 1 ,PROGRAMMED cell death 1 receptors ,PERITONEAL macrophages ,LIVER cancer - Abstract
Emerging evidence suggests that resident macrophages within tissues are enablers of tumor growth. However, a second population of resident macrophages surrounds all visceral organs within the cavities and nothing is known about these GATA6
+ large peritoneal macrophages (GLPMs) despite their ability to invade injured visceral organs by sensing danger signals. Here, we show that GLPMs invade growing metastases that breach the visceral mesothelium of the liver via the "find me signal", ATP. Depleting GLPMs either by pharmacological or genetic tools, reduces metastases growth. Apoptotic bodies from tumor cells induces programmed cell death ligand 1 (PD-L1) upregulation on GLPMs which block CD8+ T cell function. Direct targeting of GLPMs by intraperitoneal but not intravenous administration of anti-PD-L1 reduces tumor growth. Thermal ablation of liver metastases recruits huge numbers of GLPMs and enables rapid regrowth of tumors. GLPMs contribute to metastatic growth and tumor recurrence. GLPMs represent a population of fetal liver derived large peritoneal cavity Gata6+ macrophages, with the capacity to invade the tissues they surround. Here, in experimental colon cancer liver metastasis models, the authors show that GLPMs invade liver metastasis directly from the peritoneum, promoting liver metastases growth. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
6. Re-programming mouse liver-resident invariant natural killer T cells for suppressing hepatic and diabetogenic autoimmunity.
- Author
-
Umeshappa, Channakeshava Sokke, Solé, Patricia, Yamanouchi, Jun, Mohapatra, Saswat, Surewaard, Bas G. J., Garnica, Josep, Singha, Santiswarup, Mondal, Debajyoti, Cortés-Vicente, Elena, D'Mello, Charlotte, Mason, Andrew, Kubes, Paul, Serra, Pau, Yang, Yang, and Santamaria, Pere
- Abstract
Invariant NKT (iNKT) cells comprise a heterogeneous group of non-circulating, tissue-resident T lymphocytes that recognize glycolipids, including alpha-galactosylceramide (αGalCer), in the context of CD1d, but whether peripheral iNKT cell subsets are terminally differentiated remains unclear. Here we show that mouse and human liver-resident αGalCer/CD1d-binding iNKTs largely correspond to a novel Zbtb16
+ Tbx21+ Gata3+ Maflow Rorc– subset that exhibits profound transcriptional, phenotypic and functional plasticity. Repetitive in vivo encounters of these liver iNKT (LiNKT) cells with intravenously delivered αGalCer/CD1d-coated nanoparticles (NP) trigger their differentiation into immunoregulatory, IL-10+IL-21-producing Zbtb16high Mafhigh Tbx21+ Gata3+ Rorc– cells, termed LiNKTR1, expressing a T regulatory type 1 (TR1)-like transcriptional signature. This response is LiNKT-specific, since neither lung nor splenic tissue-resident iNKT cells from αGalCer/CD1d-NP-treated mice produce IL-10 or IL-21. Additionally, these LiNKTR1 cells suppress autoantigen presentation, and recognize CD1d expressed on conventional B cells to induce IL-10+IL-35-producing regulatory B (Breg) cells, leading to the suppression of liver and pancreas autoimmunity. Our results thus suggest that LiNKT cells are plastic for further functional diversification, with such plasticity potentially targetable for suppressing tissue-specific inflammatory phenomena. Invariant natural killer T (iNKT) cells are tissue-resident immune cells recognizing lipid antigens. Here the authors find that liver, but not lung nor spleen, iNKT cells alter their transcriptome upon systemic treatment of lipid nanoparticles for the induction of regulatory B cells and suppression of liver and pancreas autoimmunity in mouse models. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
7. Imaging reveals novel innate immune responses in lung, liver, and beyond*.
- Author
-
Neupane, Arpan Sharma and Kubes, Paul
- Subjects
IMMUNE response ,LIVER ,LUNGS ,LEUCOCYTES - Abstract
Highly dynamic immune responses are generated toward pathogens or injuries, in vivo. Multiple immune cell types participate in various facets of the response which leads to a concerted effort in the removal and clearance of pathogens or injured tissue and a return to homeostasis. Intravital microscopy (IVM) has been extensively utilized to unravel the dynamics of immune responses, visualizing immune cell behavior in intact living tissues, within a living organism. For instance, the phenomenon of leukocyte recruitment cascade. Importantly, IVM has led to a deep appreciation that immune cell behavior and responses in individual organs are distinct, but also can influence one another. In this review, we discuss how IVM as a tool has been used to study the innate immune responses in various tissues during homeostasis, injury, and infection. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
8. Recruited monocytes repair infections.
- Author
-
Kratofil, Rachel M. and Kubes, Paul
- Subjects
WOUND healing ,MONOCYTES ,ADIPOKINES ,INFECTION ,STAPHYLOCOCCUS aureus infections ,DIABETIC foot ,GHRELIN receptors - Abstract
UNEXPECTED ROLE OF HUNGER HORMONES IN HEALING Imaging these wounds at 14 days post-infection revealed that the wounds of monocyte-deficient mice were hypervascularised, and wounds were unable to heal at 30 days post-infection indicative of a aberrant healing and a perpetual wound in monocyte-deficient mice. I Staphylococcus aureus (S. aureus) i skin infection models have been widely used by researchers for decades in the fields of immunology and microbiology to study host-pathogen interactions. [Extracted from the article]
- Published
- 2022
- Full Text
- View/download PDF
9. Intraperitoneal microbial contamination drives post-surgical peritoneal adhesions by mesothelial EGFR-signaling.
- Author
-
Zindel, Joel, Mittner, Jonas, Bayer, Julia, April-Monn, Simon L., Kohler, Andreas, Nusse, Ysbrand, Dosch, Michel, Büchi, Isabel, Sanchez-Taltavull, Daniel, Dawson, Heather, Gomez de Agüero, Mercedes, Asahina, Kinji, Kubes, Paul, Macpherson, Andrew J., Stroka, Deborah, and Candinas, Daniel
- Subjects
TISSUE adhesions ,MICROBIAL contamination ,EPIDERMAL growth factor receptors ,EPIDERMAL growth factor ,CELL adhesion ,BACTERIAL contamination - Abstract
Abdominal surgeries are lifesaving procedures but can be complicated by the formation of peritoneal adhesions, intra-abdominal scars that cause intestinal obstruction, pain, infertility, and significant health costs. Despite this burden, the mechanisms underlying adhesion formation remain unclear and no cure exists. Here, we show that contamination of gut microbes increases post-surgical adhesion formation. Using genetic lineage tracing we show that adhesion myofibroblasts arise from the mesothelium. This transformation is driven by epidermal growth factor receptor (EGFR) signaling. The EGFR ligands amphiregulin and heparin-binding epidermal growth factor, are sufficient to induce these changes. Correspondingly, EGFR inhibition leads to a significant reduction of adhesion formation in mice. Adhesions isolated from human patients are enriched in EGFR positive cells of mesothelial origin and human mesothelium shows an increase of mesothelial EGFR expression during bacterial peritonitis. In conclusion, bacterial contamination drives adhesion formation through mesothelial EGFR signaling. This mechanism may represent a therapeutic target for the prevention of adhesions after intra-abdominal surgery. Abdominal surgery can often lead to complications including the formation of peritoneal adhesions and the molecular mechanisms underlying this process are still unknown. Here, the authors suggest that bacterial contamination drives adhesion formation through mesothelial EGFR signalling. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
10. Exploratory Evaluation of the Relationship Between iNKT Cells and Systemic Cytokine Profiles of Critically Ill Patients with Neurological Injury.
- Author
-
Scott, Brittney N. V., Kramer, Andreas H., Nguyen, Rita, Wong, Connie H. Y., Jenne, Craig N., Ruddell, Stacy, Wong, Josee, Tse, Mandy, Winston, Brent W., Soo, Andrea, Doig, Christopher J., Zygun, David A., and Kubes, Paul
- Subjects
CYTOTOXIC T cells ,CRITICALLY ill ,KILLER cells ,CYTOKINES ,INTENSIVE care units - Abstract
Background: Neurological injury can alter the systemic immune system, modifying the functional capacity of immune cells and causing a dysfunctional balance of cytokines, although mechanisms remain incompletely understood. The objective of this study was to assess the temporal relationship between changes in the activation status of circulating invariant natural killer T (iNKT) cells and the balance of plasma cytokines among critically ill patients with neurological injury. Methods: We conducted an exploratory prospective observational study of adult (18 years or older) intensive care unit (ICU) patients with acute neurological injury (n = 20) compared with ICU patients without neurological injury (n = 22) and healthy controls (n = 10). Blood samples were collected on days 1, 2, 4, 7, 14, and 28 following ICU admission to analyze the activation status of circulating iNKT cells by flow cytometry and the plasma concentration of inflammation-relevant immune mediators, including T helper 1 (T
H 1) and T helper 2 (TH 2) cytokines, by multiplex bead-based assay. Results: Invariant natural killer T cells were activated in both ICU patient groups compared with healthy controls. Neurological patients had decreased levels of multiple immune mediators, including TH 1 cytokines (interferon-γ, tumor necrosis factor-α, and interleukin-12p70), indicative of immunosuppression. This led to a greater than twofold increase in the ratio of TH 2/TH 1 cytokines early after injury (days 1 − 2) compared with healthy controls, a shift that was also observed for ICU controls. Systemic TH 2/TH 1 cytokine ratios were positively associated with iNKT cell activation in the neurological patients and negatively associated in ICU controls. These relationships were strongest for the CD4+ iNKT cell subset compared with the CD4− iNKT cell subset. The relationships to individual cytokines similarly differed between patient groups. Forty percent of the neurological patients developed an infection; however, differences for the infection subgroup were not identified. Conclusions: Critically ill patients with neurological injury demonstrated altered systemic immune profiles early after injury, with an association between activated peripheral iNKT cells and elevated systemic TH 2/TH 1 cytokine ratios. This work provides further support for a brain–immune axis and the ability of neurological injury to have far-reaching effects on the body's immune system. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
11. Protective CD4+ Th1 cell-mediated immunity is reliant upon execution of effector function prior to the establishment of the pathogen niche.
- Author
-
Hohman, Leah S., Mou, Zhirong, Carneiro, Matheus B., Ferland, Gabriel, Kratofil, Rachel M., Kubes, Paul, Uzonna, Jude E., and Peters, Nathan C.
- Subjects
CELLULAR immunity ,T cells ,TUBERCULOSIS ,TH1 cells ,LEISHMANIA ,INTRACELLULAR pathogens ,LYMPHOCYTE subsets ,VACCINE effectiveness - Abstract
Intracellular infection with the parasite Leishmania major features a state of concomitant immunity in which CD4
+ T helper 1 (Th1) cell-mediated immunity against reinfection coincides with a chronic but sub-clinical primary infection. In this setting, the rapidity of the Th1 response at a secondary site of challenge in the skin represents the best correlate of parasite elimination and has been associated with a reversal in Leishmania-mediated modulation of monocytic host cells. Remarkably, the degree to which Th1 cells are absolutely reliant upon the time at which they interact with infected monocytes to mediate their protective effect has not been defined. In the present work, we report that CXCR3-dependent recruitment of Ly6C+ Th1 effector (Th1EFF ) cells is indispensable for concomitant immunity and acute (<4 days post-infection) Th1EFF cell-phagocyte interactions are critical to prevent the establishment of a permissive pathogen niche, as evidenced by altered recruitment, gene expression and functional capacity of innate and adaptive immune cells at the site of secondary challenge. Surprisingly, provision of Th1EFF cells after establishment of the pathogen niche, even when Th1 cells were provided in large quantities, abrogated protection, Th1EFF cell accumulation and IFN-γ production, and iNOS production by inflammatory monocytes. These findings indicate that protective Th1 immunity is critically dependent on activation of permissive phagocytic host cells by preactivated Th1EFF cells at the time of infection. Author summary: Ongoing chronic infection with the intracellular parasite Leishmania major results in robust protective immunity at sites of secondary challenge. However, translation of our understanding of this protective response into an efficient vaccine has remained elusive. This is due, at least in part, to the fact that primary chronic infection maintains multiple effector and memory subsets of lymphocytes, making it difficult to determine the relative importance of any single subset and their functional properties, including the time at which they mediate their effector function. Employing parabiosis, adoptive transfer, and in-vivo blockade of effector functions followed by analysis by intravital microscopy and flow cytometry, we find that the acute availability of circulating CD4+ T helper 1 effector cells (Th1EFF ) at the time of secondary challenge is critical for the Th1 immune response to prevent L. major-mediated immunomodulation of host phagocytes and mediate protective immunity. Therefore, the present lack of effective Th1-mediated vaccines that target CD4+ memory T cell generation may be because protective Th1 immunity relies on preactivated Th1EFF cells and IFN-γ availability prior to the establishment of a pathogen niche, which occurs before these memory T cells acquire effector function. To the best of our knowledge, our observations are the first to formally demonstrate the degree to which Th1EFF cells are reliant on the time at which they interact with infected phagocytes to mediate protection and have significant implications for vaccine strategies against phagosomal infections such as Leishmania spp., Mycobacterium tuberculosis, Salmonella enterica, and Crytococcus spp.. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
12. Programmed Death Ligand 1 Is Overexpressed in Liver Macrophages in Chronic Liver Diseases, and Its Blockade Improves the Antibacterial Activity Against Infections.
- Author
-
Pose, Elisa, Coll, Mar, Martínez‐Sánchez, Celia, Zeng, Zhutian, Surewaard, Bas G. J., Català, Cristina, Velasco‐de Andrés, María, Lozano, Juan José, Ariño, Sílvia, Fuster, David, Niñerola‐Bazán, Aida, Graupera, Isabel, Muñoz, Érica, Lozano, Francisco, Sancho‐Bru, Pau, Kubes, Paul, and Ginès, Pere
- Published
- 2021
- Full Text
- View/download PDF
13. Tacrolimus Impairs Kupffer Cell Capacity to Control Bacteremia: Why Transplant Recipients Are Susceptible to Infection.
- Author
-
Deppermann, Carsten, Peiseler, Moritz, Zindel, Joel, Zbytnuik, Lori, Lee, Woo‐Yong, Pasini, Elisa, Baciu, Cristina, Matelski, John, Lee, Yun, Kumar, Deepali, Humar, Atul, Surewaard, Bas, Kubes, Paul, and Bhat, Mamatha
- Published
- 2021
- Full Text
- View/download PDF
14. Paracoccidioides brasiliensis Releases a DNase-Like Protein That Degrades NETs and Allows for Fungal Escape.
- Author
-
Zonta, Yohan Ricci, Dezen, Ana Laura Ortega, Della Coletta, Amanda Manoel, Yu, Kaio Shu Tsyr, Carvalho, Larissa, Santos, Leandro Alves dos, Deprá, Igor de Carvalho, Kratofil, Rachel M., Willson, Michelle Elizabeth, Zbytnuik, Lori, Kubes, Paul, Ximenes, Valdecir Farias, and Dias-Melicio, Luciane Alarcão
- Subjects
PARACOCCIDIOIDES brasiliensis ,DNA structure ,GENES ,MYCOSES ,PROTEINS ,COCCIDIOIDOMYCOSIS - Abstract
Paracoccidioidomycosis is a systemic fungal disease, considered endemic in Latin America. Its etiological agents, fungi of the Paracoccidioides complex, have restricted geographic habitat, conidia as infecting form, and thermo-dimorphic characteristics. Polymorphonuclear neutrophils (PMNs) are responsible for an important defense response against fungus, releasing Neutrophil Extracellular Traps (NETs), which can wrap and destroy the yeasts. However, it has been described that some pathogens are able to evade from these DNA structures by releasing DNase as an escape mechanism. As different NETs patterns have been identified in PMNs cultures challenged with different isolates of Paracoccidioides brasiliensis , the general objective of this study was to identify if different patterns of NETs released by human PMNs challenged with Pb18 (virulent) and Pb265 (avirulent) isolates would be correlated with fungal ability to produce a DNase-like protein. To this end, PMNs from healthy subjects were isolated and challenged in vitro with both fungal isolates. The production, release, and conformation of NETs in response to the fungi were evaluated by Confocal Microscopy, Scanning Microscopy, and NETs Quantification. The identification of fungal DNase production was assessed by DNase TEST Agar, and the relative gene expression for hypothetical proteins was investigated by RT-qPCR, whose genes had been identified in the fungal genome in the GenBank (PADG_11161 and PADG_08285). It was possible to verify the NETs release by PMNs, showing different NETs formation when in contact with different isolates of the fungus. The Pb18 isolate induced the release of looser, larger, and more looking like degraded NETs compared to the Pb265 isolate, which induced the release of denser and more compact NETs. DNase TEST Agar identified the production of a DNase-like protein, showing that only Pb18 showed the capacity to degrade DNA in these plates. Besides that, we were able to identify that both PADG_08528 and PADG_11161 genes were more expressed during interaction with neutrophil by the virulent isolate, being PADG_08528 highly expressed in these cultures, demonstrating that this gene could have a greater contribution to the production of the protein. Thus, we identified that the virulent isolate is inducing more scattered and loose NETs, probably by releasing a DNase-like protein. This factor could be an important escape mechanism used by the fungus to escape the NETs action. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
15. Acute skin exposure to ultraviolet light triggers neutrophil-mediated kidney inflammation.
- Author
-
Skopelja-Gardner, Sladjana, Tai, Joyce, Xizhang Sun, Tanaka, Lena, Kuchenbecker, James A., Snyder, Jessica M., Kubes, Paul, Mustelin, Tomas, and Elkon, Keith B.
- Subjects
ULTRAVIOLET radiation ,TYPE I interferons ,INFLAMMATORY mediators ,KIDNEYS ,SKIN - Abstract
Photosensitivity to ultraviolet (UV) light affects up to ~80% of lupus patients. Sunlight exposure can exacerbate local as well as systemic manifestations of lupus, including nephritis, by mechanisms that are poorly understood. Here, we report that acute skin exposure to UV light triggers a neutrophil-dependent injury response in the kidney characterized by upregulated expression of endothelial adhesion molecules as well as inflammatory and injury markers associated with transient proteinuria. We showed that UV light stimulates neutrophil migration not only to the skin but also to the kidney in an IL-17A-dependent manner. Using a photoactivatable lineage tracing approach, we observed that a subset of neutrophils found in the kidney had transited through UV light-exposed skin, suggesting reverse transmigration. Besides being required for the renal induction of genes encoding mediators of inflammation (vcam-1, s100A9, and Il-1b) and injury (lipocalin-2 and kim-1), neutrophils significantly contributed to the kidney type I interferon signature triggered by UV light. Together, these findings demonstrate that neutrophils mediate subclinical renal inflammation and injury following skin exposure to UV light. Of interest, patients with lupus have subpopulations of blood neutrophils and low-density granulocytes with similar phenotypes to reverse transmigrating neutrophils observed in the mice post-UV exposure, suggesting that these cells could have transmigrated from inflamed tissue, such as the skin. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
16. A molecular map of murine lymph node blood vascular endothelium at single cell resolution.
- Author
-
Brulois, Kevin, Rajaraman, Anusha, Szade, Agata, Nordling, Sofia, Bogoslowski, Ania, Dermadi, Denis, Rahman, Milladur, Kiefel, Helena, O'Hara, Edward, Koning, Jasper J., Kawashima, Hiroto, Zhou, Bin, Vestweber, Dietmar, Red-Horse, Kristy, Mebius, Reina E., Adams, Ralf H., Kubes, Paul, Pan, Junliang, and Butcher, Eugene C.
- Subjects
VASCULAR endothelium ,GENE mapping ,LYMPH nodes ,VASCULAR endothelial cells ,LYMPHOID tissue - Abstract
Blood vascular endothelial cells (BECs) control the immune response by regulating blood flow and immune cell recruitment in lymphoid tissues. However, the diversity of BEC and their origins during immune angiogenesis remain unclear. Here we profile transcriptomes of BEC from peripheral lymph nodes and map phenotypes to the vasculature. We identify multiple subsets, including a medullary venous population whose gene signature predicts a selective role in myeloid cell (vs lymphocyte) recruitment to the medulla, confirmed by videomicroscopy. We define five capillary subsets, including a capillary resident precursor (CRP) that displays stem cell and migratory gene signatures, and contributes to homeostatic BEC turnover and to neogenesis of high endothelium after immunization. Cell alignments show retention of developmental programs along trajectories from CRP to mature venous and arterial populations. Our single cell atlas provides a molecular roadmap of the lymph node blood vasculature and defines subset specialization for leukocyte recruitment and vascular homeostasis. The origin and diversity of blood vascular endothelial cells (BEC) in lymphoid tissues is unclear. Here, the authors profile murine BECs from peripheral lymph nodes by single cell analysis and identify subsets of cells specialised for immune cell recruitment and vascular homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
17. Chemotaxing neutrophils enter alternate branches at capillary bifurcations.
- Author
-
Wang, Xiao, Hossain, Mokarram, Bogoslowski, Ania, Kubes, Paul, and Irimia, Daniel
- Subjects
NEUTROPHILS ,MICROBIAL invasiveness ,TRAFFIC congestion ,MICROFLUIDIC devices ,TRAFFIC patterns ,LYMPHOCYTES - Abstract
Upon tissue injury or microbial invasion, a large number of neutrophils converge from blood to the sites of injury or infection in a short time. The migration through a limited number of paths through tissues and capillary networks seems efficient and 'traffic jams' are generally avoided. However, the mechanisms that guide efficient trafficking of large numbers of neutrophils through capillary networks are not well understood. Here we show that pairs of neutrophils arriving closely one after another at capillary bifurcations migrate to alternating branches in vivo and in vitro. Perturbation of chemoattractant gradients and the increased hydraulic resistance induced by the first neutrophil in one branch biases the migration of the following neutrophil towards the other branch. These mechanisms guide neutrophils to efficiently navigate through capillary networks and outline the effect of inter-neutrophil interactions during migration on overall lymphocyte trafficking patterns in confined environments. Neutrophils mobilize rapidly and travel through the vasculature and microcirculation en masse in response to inflammatory stimuli. Here the authors use a microfluidic device and intravital microscopy to show neutrophils move through tissues in a highly ordered pattern, taking turns to file into alternate branches at bifurcations. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
18. Perivascular localization of macrophages in the intestinal mucosa is regulated by Nr4a1 and the microbiome.
- Author
-
Honda, Masaki, Surewaard, Bas G. J., Watanabe, Mayuki, Hedrick, Catherine C., Lee, Woo-Yong, Brown, Kirsty, McCoy, Kathy D., and Kubes, Paul
- Subjects
INTESTINAL mucosa ,SMALL intestine ,INTESTINES ,LARGE intestine ,INTESTINAL injuries ,MACROPHAGES ,GLYCOCALYX - Abstract
While the ontogeny and recruitment of the intestinal monocyte/macrophage lineage has been studied extensively, their precise localization and function has been overlooked. Here we show by imaging the murine small and large intestines in steady-state that intestinal CX3CR1
+ macrophages form an interdigitated network intimately adherent to the entire mucosal lamina propria vasculature. The macrophages form contacts with each other, which are disrupted in the absence of microbiome, monocyte recruitment (Ccr2−/− ), or monocyte conversion (Nr4a1−/− ). In dysbiosis, gaps exist between the perivascular macrophages correlating with increased bacterial translocation from the lamina propria into the bloodstream. The recruitment of monocytes and conversion to macrophages during intestinal injury is also dependent upon CCR2, Nr4a1 and the microbiome. These findings demonstrate a relationship between microbiome and the maturation of lamina propria perivascular macrophages into a tight anatomical barrier that might function to prevent bacterial translocation. These cells are also critical for emergency vascular repair. Lamina propria macrophages are at the frontline of defense against intestinal pathogens. Here the authors reveal that CCR2 and NR4A1-dependent CX3CR1+ macrophages form a dense network around the vessels in the lamina propria, and implicate this anatomical structure into prevention of systemic bacterial dissemination. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
19. DAMPs, PAMPs, and LAMPs in Immunity and Sterile Inflammation.
- Author
-
Zindel, Joel and Kubes, Paul
- Published
- 2020
- Full Text
- View/download PDF
20. Extracellular vesicles selectively mobilize splenic neutrophils.
- Author
-
Panda, Rachita and Kubes, Paul
- Subjects
EXTRACELLULAR vesicles ,NEUTROPHILS ,HEART failure - Abstract
This editorial refers to 'Rapid neutrophil mobilization by VCAM-11 endothelial cell-derived extracellular vesicles', by N. Akbar I et al i . https://doi.org/10.1093/cvr/cvac012. While single-cell RNA sequencing has certainly highlighted many different neutrophil subsets simplistically, there is likely an anti-microbial and a repair neutrophil subset. [Extracted from the article]
- Published
- 2023
- Full Text
- View/download PDF
21. Unraveling the host's immune response to infection: Seeing is believing.
- Author
-
Scott, Brittney N.V., Sarkar, Tina, Kratofil, Rachel M., Kubes, Paul, and Thanabalasuriar, Ajitha
- Subjects
IMMUNE response ,BACTERIAL diseases ,NATURAL immunity ,THERAPEUTICS ,INFECTION - Abstract
It has long been appreciated that understanding the interactions between the host and the pathogens that make us sick is critical for the prevention and treatment of disease. As antibiotics become increasingly ineffective, targeting the host and specific bacterial evasion mechanisms are becoming novel therapeutic approaches. The technology used to understand host‐pathogen interactions has dramatically advanced over the last century. We have moved away from using simple in vitro assays focused on single‐cell events to technologies that allow us to observe complex multicellular interactions in real time in live animals. Specifically, intravital microscopy (IVM) has improved our understanding of infection, from viral to bacterial to parasitic, and how the host immune system responds to these infections. Yet, at the same time it has allowed us to appreciate just how complex these interactions are and that current experimental models still have a number of limitations. In this review, we will discuss the advances in vivo IVM has brought to the study of host‐pathogen interactions, focusing primarily on bacterial infections and innate immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
22. Innate immune cells orchestrate the repair of sterile injury in the liver and beyond.
- Author
-
Hossain, Mokarram and Kubes, Paul
- Subjects
NATURAL immunity ,INFLAMMATION treatment ,LIVER injuries ,NEUTROPHILS ,MONOCYTES ,MACROPHAGES - Abstract
There is a close association between inflammation and sterile injury, however not all sterile injuries are the same. While a regulated inflammatory response is crucial for proper healing, a dysregulated or nonterminating response leads to disrepair. While immune cells are thought to contribute to the disrepair, they may also be critical for proper healing and as such, their actions may dictate the end result. In all forms of sterile injury, release of damage‐associated molecular patterns from necrotic cells causes robust recruitment of innate immune cells. The subsequent release of toxic mediators from immune cells is thought to be damaging in non‐resolving sterile injuries in which the dysregulated immune response leads to chronic inflammatory disease. While similar mediators may be released from immune cells in resolution of acute injury, the spatial localization, timing, and self‐termination may all be critical. In this review, we summarize the recent advances in our understanding of the temporal and spatial recruitment of various innate immune cells that beget appropriate healing of acute injuries. Where possible we try to compare this appropriate response to dysregulated sterile injuries in an attempt to identify novel therapeutic targets. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
23. Exploring the complex role of chemokines and chemoattractants in vivo on leukocyte dynamics.
- Author
-
David, Bruna A. and Kubes, Paul
- Subjects
G protein coupled receptors ,INFLAMMATORY mediators ,CELL migration ,DRUG side effects ,LEUCOCYTES - Abstract
Summary: Chemotaxis is fundamental for leukocyte migration in immunity and inflammation and contributes to the pathogenesis of many human diseases. Although chemokines and various other chemoattractants were initially appreciated as important mediators of acute inflammation, in the past years they have emerged as critical mediators of cell migration during immune surveillance, organ development, and cancer progression. Such advances in our knowledge in chemokine biology have paved the way for the development of specific pharmacological targets with great therapeutic potential. Chemoattractants may belong to different classes, including a complex chemokine system of approximately 50 endogenous molecules that bind to G protein‐coupled receptors, which are expressed by a wide variety of cell types. Also, an unknown number of other chemoattractants may be generated by pathogens and damaged/dead cells. Therefore, blocking chemotaxis without causing side effects is an extremely challenging task. In this review, we focus on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the whole organ level in homeostasis, inflammation, and infection. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
24. THE NEUTROPHIL’S ROLE DURING HEALTH AND DISEASE.
- Author
-
Pei Xiong Liew and Kubes, Paul
- Abstract
Neutrophils have always been considered as uncomplicated front-line troopers of the innate immune system equipped with limited proinflammatory duties. Yet recently, the role of the neutrophil has been undergoing a rejuvenation of sorts. Neutrophils are now considered complex cells capable of a significant array of specialized functions, and as an effector of the innate immune response, they are able to regulate many processes such as acute injury and repair, cancer, autoimmunity, and chronic inflammatory processes. Furthermore, evidence exists to indicate that neutrophils also contribute to adaptive immunity by aiding the development of specific adaptive immune responses or guiding the subsequent adaptive immune response. With this revived interest in neutrophils and their many novel functions, it is prudent to review what is currently known about neutrophils and, even more importantly, understand what information is lacking. We discuss the essential features of the neutrophil, from its origins, lifespan, subsets, margination and sequestration of the neutrophil to the death of the neutrophil. We highlight neutrophil recruitment to both infected and injured tissues and outline differences in recruitment of neutrophils between different tissues. Finally, we examine how neutrophils use different mechanisms to either bolster protective immune responses or negatively cause pathological outcomes at different locations. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
25. Neutrophils: New insights and open questions.
- Author
-
Ley, Klaus, Hoffman, Hal M., Kubes, Paul, Cassatella, Marco A., Zychlinsky, Arturo, Hedrick, Catherine C., and Catz, Sergio D.
- Subjects
NEUTROPHILS ,MYELOSUPPRESSION ,PARASITES ,VIRUSES ,IMMUNE system - Abstract
Neutrophils are the first line of defense against bacteria and fungi and help combat parasites and viruses. They are necessary for mammalian life, and their failure to recover after myeloablation is fatal. Neutrophils are short-lived, effective killing machines. Their life span is significantly extended under infectious and inflammatory conditions. Neutrophils take their cues directly from the infectious organism, from tissue macrophages and other elements of the immune system. Here, we review how neutrophils traffic to sites of infection or tissue injury, how they trap and kill bacteria, how they shape innate and adaptive immune responses, and the pathophysiology of monogenic neutrophil disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
26. Start a fire, kill the bug: The role of platelets in inflammation and infection.
- Author
-
Deppermann, Carsten and Kubes, Paul
- Subjects
BLOOD platelets ,KUPFFER cells ,INFECTION ,MACROPHAGES ,NEUTROPHILS ,THROMBOSIS ,HEMOSTASIS - Abstract
Platelets are the main players in thrombosis and hemostasis; however they also play important roles during inflammation and infection. Through their surface receptors, platelets can directly interact with pathogens and immune cells. Platelets form complexes with neutrophils to modulate their capacities to produce reactive oxygen species or form neutrophil extracellular traps. Furthermore, they release microbicidal factors and cytokines that kill pathogens and influence the immune response, respectively. Platelets also maintain the vascular integrity during inflammation by a mechanism that is different from classical platelet activation. In this review we summarize the current knowledge about how platelets interact with the innate immune system during inflammation and infection and highlight recent advances in the field. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
27. Macrophages play an essential role in trauma-induced sterile inflammation and tissue repair.
- Author
-
Peiseler, Moritz and Kubes, Paul
- Subjects
INJURY complications ,CELL membranes ,HOMEOSTASIS ,INFLAMMATION ,MACROPHAGES ,MONOCYTES ,NECROSIS ,SEPSIS ,WOUND healing ,WOUNDS & injuries ,PHENOTYPES ,CATHELICIDINS ,SYSTEMIC inflammatory response syndrome - Abstract
Severe trauma is accompanied by a profound activation of the immune system. Patients with polytrauma develop systemic inflammatory response syndrome (SIRS) and often sepsis, which contributes substantially to high mortality of this condition. On a cellular level, necrosis and loss of plasma membrane integrity lead to the release of endogenous “damage-associated molecular patterns” (DAMPs) as danger signals, which in turn activate innate immune cells. Inflammation that occurs in the absence of invading pathogens has been termed sterile inflammation and trauma with tissue damage represents an acute form of sterile inflammation. Macrophages are a heterogeneous group of phagocytes of the innate immune system and serve as sentinels to detect loss of tissue integrity. Macrophages show a remarkable plasticity and undergo phenotypical changes in response to injury and repair. Under basal conditions, tissue-resident macrophages are distributed in various organ systems and have critical functions in tissue development and the maintenance of homeostasis. Inflammatory conditions, such as major trauma, lead to the rapid recruitment of blood-derived monocytes that mature into macrophages as well as direct recruitment of macrophages from the cavity that surrounds the injured organ. This leads to augmentation of the pool of tissue-resident macrophages. Besides their essential role in sensing tissue damage and initiating inflammation, macrophages contribution critically to tissue repair and wound healing, ultimately allowing full restoration. Dysregulated sterile inflammation and defective healing result in chronic inflammatory disease with persistent tissue damage. In this review, we summarize the cellular and molecular mechanisms that lead to activation of sterile inflammation, recruitment of immune cells and initiation of wound healing. We focus on the pivotal role of macrophages played in this context. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
28. Neutrophil heterogeneity: Bona fide subsets or polarization states?
- Author
-
Deniset, Justin F. and Kubes, Paul
- Subjects
NEUTROPHILS ,IMMUNE system ,GRANULOCYTES ,SUPPRESSOR cells ,INFLAMMATION - Abstract
Abstract: Neutrophils are key components of the innate immune system that play important roles during infection, injury, and chronic disease. In recent years, neutrophil heterogeneity has become an emerging focus with accumulating evidence of neutrophil populations with distinct functions under both steady‐state and pathologic conditions. Despite these advances, it remains unclear whether these different populations represent bona fide subsets or simply activation/polarization states in response to local cues. In this review, we summarize the varied neutrophils populations that have been described under both basal and during inflammation. We discuss the evidence that supports the existence of neutrophils subsets. Finally, we identify potential gaps in our knowledge that may further advance our current understanding of neutrophil heterogeneity. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
29. Immune Responses in the Liver.
- Author
-
Kubes, Paul and Jenne, Craig
- Abstract
The liver is a key, frontline immune tissue. Ideally positioned to detect pathogens entering the body via the gut, the liver appears designed to detect, capture, and clear bacteria, viruses, and macromolecules. Containing the largest collection of phagocytic cells in the body, this organ is an important barrier between us and the outside world. Importantly, as portal blood also transports a large number of foreign but harmless molecules (e.g., food antigens), the liver's default immune status is anti-inflammatory or immunotolerant; however, under appropriate conditions, the liver is able to mount a rapid and robust immune response. This balance between immunity and tolerance is essential to liver function. Excessive inflammation in the absence of infection leads to sterile liver injury, tissue damage, and remodeling; insufficient immunity allows for chronic infection and cancer. Dynamic interactions between the numerous populations of immune cells in the liver are key to maintaining this balance and overall tissue health. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
30. Neutrophils recruited through high endothelial venules of the lymph nodes via PNAd intercept disseminating Staphylococcus aureus.
- Author
-
Bogoslowski, Ania, Butcher, Eugene C., and Kubes, Paul
- Subjects
STAPHYLOCOCCUS aureus infections ,COMMUNITY-acquired infections ,NEUTROPHILS ,LYMPH nodes ,SKIN infections ,BACTEREMIA - Abstract
Staphylococcus aureus is a skin- and respiratory tract-colonizing bacterium and is the leading cause of community-acquired skin infections. Dissemination of these bacteria into systemic circulation causes bacteremia, which has a high mortality rate. Therefore, understanding the immunologic barriers that prevent dissemination is critical to developing novel treatments. In this study, we demonstrate that an S. aureus breach across skin leads to some migration of the pathogen to the draining lymph node, but no further. While subcapsular sinus (SCS) macrophage in lymph nodes were important in detaining S. aureus, a rapid complement-dependent neutrophil recruitment (independent of the SCS macrophage) via high endothelial venules (HEVs) resulted in high numbers of neutrophils that intercepted the bacteria in the lymph nodes. Peripheral Node Addressin together with its two ligands, L-selectin and platelet P-selectin, are critical for recruiting neutrophils via the HEVs. Almost no neutrophils entered the lymph nodes via lymphatics. Neutrophils actively phagocytosed S. aureus and helped sterilize the lymph nodes and prevent dissemination to blood and other organs. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
31. The enigmatic neutrophil: what we do not know.
- Author
-
Kubes, Paul
- Subjects
NEUTROPHILS ,IMMUNOLOGY of inflammation ,CELL differentiation ,IMMUNE response ,CELL death - Abstract
The neutrophil appears to be undergoing a renaissance of sorts. While it was for many years thought to be a killing machine brought into tissues to eradicate pathogens, it is now being implicated in many other processes, ranging from acute injury and repair, chronic inflammatory processes, cancer and auto-immunity. Not only is it an effector of the innate immune response, it appears to also potentially contribute to adaptive immunity, implicated in either contributing to the development of specific adaptive immune responses or perhaps even instructing and directing certain adaptive immune responses. With this renewed interest in the neutrophil and its numerous new functions, it is worth examining not what we know but rather what we do not know and what still needs to be more thoroughly examined. In this review, consideration is given to such topics as neutrophil subtypes, neutrophil differentiation, neutrophil as a director of immunity, neutrophil residency and ultimately death of the neutrophil. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
32. Transient von Willebrand factor-mediated platelet influx stimulates liver regeneration after partial hepatectomy in mice.
- Author
-
Kirschbaum, Marc, Jenne, Craig N., Veldhuis, Zwanida J., Sjollema, Klaas A., Lenting, Peter J., Giepmans, Ben N. G., Porte, Robert J., Kubes, Paul, Denis, Cécile V., and Lisman, Ton
- Subjects
LIVER regeneration ,LIVER diseases ,HEPATECTOMY ,LIVER surgery ,VON Willebrand disease ,GENETICS - Abstract
Background & Aims In addition to their function in thrombosis and haemostasis, platelets play an important role in the stimulation of liver regeneration. It has been suggested that platelets deliver mitogenic cargo to the regenerating liver, and accumulation of platelets in the regenerating liver has been demonstrated. We studied kinetics of platelet influx in the regenerating liver and investigated the signal that initiates platelet influx. Methods We visualized platelets in the liver remnant after partial hepatectomy in mice using intravital microscopy and assessed liver regeneration by examination of liver/body weight ratio and the number of proliferating hepatocytes examined by immunohistochemistry. Results We demonstrated rapid but transient platelet influx into the liver remnant after a partial liver resection. Liver regeneration in thrombocytopenic mice was substantially impaired as evidenced by a reduced liver-to-body weight ratio and decreased numbers of proliferating hepatocytes at day 3 compared to mice with normal platelet counts. In contrast, liver regeneration was only mildly impaired when thrombocytopaenia was induced 2 hours after partial liver resection. Platelet influx into the liver remnant was virtually absent in the presence of an antibody to von Willebrand factor ( VWF) suggesting that VWF release from liver sinusoidal endothelial cells mediates platelet influx. Additionally, liver regeneration in mice deficient in VWF was markedly impaired. Conclusions A rapid but transient VWF-dependent platelet influx into the liver remnant drives platelet-mediated liver regeneration. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
33. Visualizing the function and fate of neutrophils in sterile injury and repair.
- Author
-
Jing Wang, Hossain, Mokarram, Thanabalasuriar, Ajitha, Gunzer, Matthias, Meininger, Cynthia, and Kubes, Paul
- Published
- 2017
- Full Text
- View/download PDF
34. PKN1 Directs Polarized RAB21 Vesicle Trafficking via RPH3A and Is Important for Neutrophil Adhesion and Ischemia-Reperfusion Injury.
- Author
-
Yuan, Qianying, Ren, Chunguang, Xu, Wenwen, Petri, Björn, Zhang, Jiasheng, Zhang, Yong, Kubes, Paul, Wu, Dianqing, and Tang, Wenwen
- Abstract
Summary Polarized vesicle transport plays an important role in cell polarization, but the mechanisms underlying this process and its role in innate immune responses are not well understood. Here, we describe a phosphorylation-regulated polarization mechanism that is important for neutrophil adhesion to endothelial cells during inflammatory responses. We show that the protein kinase PKN1 phosphorylates RPH3A, which enhances binding of RPH3A to guanosine triphosphate (GTP)-bound RAB21. These interactions are important for polarized localization of RAB21 and RPH3A in neutrophils, which leads to PIP5K1C90 polarization. Consistent with the roles of PIP5K1C90 polarization, the lack of PKN1 or RPH3A impairs neutrophil integrin activation, adhesion to endothelial cells, and infiltration in inflammatory models. Furthermore, myeloid-specific loss of PKN1 decreases tissue injury in a renal ischemia-reperfusion model. Thus, this study characterizes a mechanism for protein polarization in neutrophils and identifies a potential protein kinase target for therapeutic intervention in reperfusion-related tissue injury. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
35. CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions.
- Author
-
Vanheule, Vincent, Boff, Daiane, Mortier, Anneleen, Janssens, Rik, Petri, Björn, Kolaczkowska, Elzbieta, Kubes, Paul, Berghmans, Nele, Struyf, Sofie, Kungl, Andreas J., Teixeira, Mauro Martins, Amaral, Flavio Almeida, and Proost, Paul
- Subjects
CHEMOKINES ,NEUTROPHILS ,CELL migration ,GLYCOSAMINOGLYCANS ,IN vivo studies - Abstract
Several acute and chronic inflammatory diseases are driven by accumulation of activated leukocytes due to enhanced chemokine expression. In addition to specific G protein-coupled receptor-dependent signaling, chemokine-glycosaminoglycan (GAG) interactions are important for chemokine activity in vivo. Therefore, the GAG-chemokine interaction has been explored as target for inhibition of chemokine activity. It was demonstrated that CXCL9(74-103) binds with high affinity to GAGs, competed with active chemokines for GAG binding and thereby inhibited CXCL8- and monosodium urate (MSU) crystal-induced neutrophil migration to joints. To evaluate the affinity and specificity of the COOH-terminal part of CXCL9 toward different GAGs in detail, we chemically synthesized several COOH-terminal CXCL9 peptides including the shorter CXCL9(74-93). Compared to CXCL9(74-103), CXCL9(74-93) showed equally high affinity for heparin and heparan sulfate (HS), but lower affinity for binding to chondroitin sulfate (CS) and cellular GAGs. Correspondingly, both peptides competed with equal efficiency for CXCL8 binding to heparin and HS but not to cellular GAGs. In addition, differences in anti-inflammatory activity between both peptides were detected in vivo. CXCL8-induced neutrophil migration to the peritoneal cavity and to the knee joint were inhibited with similar potency by intravenous or intraperitoneal injection of CXCL9(74-103) or CXCL9(74-93), but not by CXCL9(86-103). In contrast, neutrophil extravasation in the MSU crystal-induced gout model, in which multiple chemoattractants are induced, was not affected by CXCL9(74-93). This could be explained by (1) the lower affinity of CXCL9(74-93) for CS, the most abundant GAG in joints, and (2) by reduced competition with GAG binding of CXCL1, the most abundant ELR+ CXC chemokine in this gout model. Mechanistically we showed by intravital microscopy that fluorescent CXCL9 (74-103) coats the vessel wall in vivo and that CXCL9(74-103) inhibits CXCL8-induced adhesion of neutrophils to the vessel wall in the murine cremaster muscle model. Thus, both affinity and specificity of chemokines and the peptides for different GAGs and the presence of specific GAGs in different tissues will determine whether competition can occur. In summary, both CXCL9 peptides inhibited neutrophil migration in vivo through interference with GAG interactions in several animal models. Shortening CXCL9(74-103) from the COOH-terminus limited its GAG-binding spectrum. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
36. The lung is a host defense niche for immediate neutrophil-mediated vascular protection.
- Author
-
Yipp, Bryan G., Jung Hwan Kim, Lima, Ronald, Zbytnuik, Lori D., Petri, Bjӧrn, Swanlund, Nick, Ho, May, Szeto, Vivian G., Tak, Tamar, Koenderman, Leo, Pickkers, Peter, Tool, Anton T. J., Kuijpers, Taco W., van den Berg, Timo K., Looney, Mark R., Krummel, Matthew F., and Kubes, Paul
- Abstract
Bloodstream infection is a hallmark of sepsis, a medically emergent condition requiring rapid treatment. However, up-regulation of host defense proteins through Toll-like receptors (TLRs) and nuclear factor κB requires hours after endotoxin detection. Using confocal pulmonary intravital microscopy, we identified that the lung provides a TLR4–Myd88 (myeloid differentiation primary response gene 88)–dependent and abl tyrosine kinase–dependent niche for immediate CD11b-dependent neutrophil responses to endotoxin and Gram-negative bloodstream pathogens. In an in vivo model of bacteremia, neutrophils crawled to and rapidly phagocytosed Escherichia coli sequestered to the lung endothelium. Therefore, the lung capillaries provide a vascular defensive niche whereby endothelium and neutrophils cooperate for immediate detection and capture of disseminating pathogens. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
37. Prolonged Activation of Invariant Natural Killer T Cells and TH2-Skewed Immunity in Stroke Patients.
- Author
-
Wong, Connie H. Y., Jenne, Craig N., Tam, Patrick P., Léger, Caroline, Venegas, Andres, Ryckborst, Karla, Hill, Michael D., Kubes, Paul, Meisel, Andreas, and Planas, Anna M.
- Subjects
STROKE patients ,T cells ,IMMUNE response ,PHYSIOLOGY - Abstract
Background: Infection is highly prevalent and contribute significantly to mortality of stroke patients. In addition to the well described robust systemic lymphocytopenia and skewed T helper 2 (T
H 2)-immunity after stroke, emerging experimental evidence demonstrate that the development of infection poststroke is attributed by the activation of invariant natural killer T (iNKT) cells. In this prospective study, we examined the levels of a broad spectrum of inflammatory mediators, the activation status of iNKT cell in the blood of patients with various degree of stroke severity, and investigate whether these parameters differ in patients who later develop poststroke infections. Methods and results: We obtained blood from stroke patients and matching controls to perform flow cytometry and multiplex measurement of inflammatory mediators. Our data suggest a pronounced activation of iNKT cells in stroke patients as compared with matched Healthy and Hospital control patients. The magnitude of iNKT activation is positively correlated with the severity of stroke, supporting the hypothesis that iNKT cells may contribute in the modulation of the host immune response after stroke-associated brain injury. In addition, stroke severity is closely correlated with decreased TH 1/TH 2 ratio, increased production of interleukin (IL)-10, with infected stroke patients showing exacerbated production of IL-10. Conclusion: Stroke triggers a robust and sustained shift in systemic immunity in patients, including specific lymphopenia, robust activation of iNKT cells, systemic production of IL-10, and a prolonged TH 2-skewed immunity, all are potential contributors to severe immune suppression seen in patients after stroke. Future studies with large sample size will provide potential causality relationship insights. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
38. Monocyte Conversion During Inflammation and Injury.
- Author
-
Kratofil, Rachel M., Kubes, Paul, and Deniset, Justin F.
- Published
- 2017
- Full Text
- View/download PDF
39. Pondering neutrophil extracellular traps with healthy skepticism.
- Author
-
Nauseef, William M. and Kubes, Paul
- Subjects
NEUTROPHILS ,SKEPTICISM ,CYTOLOGY ,NUCLEAR DNA ,HISTONES - Abstract
The authors engage in a dialogue that evaluates critically the state of the study of neutrophil extracellular traps (NETs), a phenomenon currently the object of considerable interest, with the goal of identifying those aspects that merit clarification in order to assign the process its proper place in our current understanding of cell biology. Since the seminal observations in the Zychlinsky laboratory that described the extrusion of filaments of nuclear DNA associated with histones and granule proteins from neutrophils stimulated in vitro, many investigators have examined the phenomenon of NET formation in numerous and diverse settings. However, an overview of work in this rapidly growing field prompts several fundamental questions about NETs, including their precise composition, the mechanisms by which they arise, their clinical relevance, and the interrelationship of those observed in vitro and in vivo. In this discussion, the authors challenge interpretation of data from some experimental settings and provide recommendations for specific studies that would address the concerns raised, improve understanding of the biological relevance of NETs, and strengthen the field. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
40. iNKT Cell Emigration out of the Lung Vasculature Requires Neutrophils and Monocyte-Derived Dendritic Cells in Inflammation.
- Author
-
Thanabalasuriar, Ajitha, Neupane, Arpan S., Wang, Jing, Krummel, Matthew F., and Kubes, Paul
- Abstract
Summary iNKT cells are a subset of innate T cells that recognize glycolipids presented on CD1d molecules and protect against bacterial infections, including S. pneumoniae . Using lung intravital imaging, we examined the behavior and mechanism of pulmonary iNKT cell activation in response to the specific iNKT cell ligand α-galactosylceramide or S. pneumoniae infection. In untreated mice, the major fraction of iNKT cells resided in the vasculature, but a small critical population resided in the extravascular space in proximity to monocyte-derived DCs. Administration of either α-GalCer or S. pneumoniae induced CD1d-dependent rapid recruitment of neutrophils out of the vasculature. The neutrophils guided iNKT cells from the lung vasculature via CCL17. Depletion of monocyte-derived DCs abrogated both the neutrophil and subsequent iNKT cell extravasation. Moreover, impairing iNKT cell recruitment by blocking CCL17 increased susceptibility to S. pneumoniae infection, suggesting a critical role for the influx of iNKT cells in host defense. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
41. Intravital Imaging of Vascular Transmigration by the Lyme Spirochete: Requirement for the Integrin Binding Residues of the B. burgdorferi P66 Protein.
- Author
-
Kumar, Devender, Ristow, Laura C., Shi, Meiqing, Mukherjee, Priyanka, Caine, Jennifer A., Lee, Woo-Yong, Kubes, Paul, Coburn, Jenifer, and Chaconas, George
- Subjects
INTEGRIN genetics ,LEUCOCYTES ,FIBRONECTIN genetics ,GLYCOSAMINOGLYCANS ,BACTERIAL adhesins ,KILLER cells - Abstract
Vascular extravasation, a key step in systemic infection by hematogenous microbial pathogens, is poorly understood, but has been postulated to encompass features similar to vascular transmigration by leukocytes. The Lyme disease spirochete can cause a variety of clinical manifestations, including arthritis, upon hematogenous dissemination. This pathogen encodes numerous surface adhesive proteins (adhesins) that may promote extravasation, but none have yet been implicated in this process. In this work we report the novel use of intravital microscopy of the peripheral knee vasculature to study transmigration of the Lyme spirochete in living Cd1d
-/- mice. In the absence of iNKT cells, major immune modulators in the mouse joint, spirochetes that have extravasated into joint-proximal tissue remain in the local milieu and can be enumerated accurately. We show that BBK32, a fibronectin and glycosaminoglycan adhesin of B. burgdorferi involved in early steps of endothelial adhesion, is not required for extravasation from the peripheral knee vasculature. In contrast, almost no transmigration occurs in the absence of P66, an outer membrane protein that has porin and integrin adhesin functions. Importantly, P66 mutants specifically defective in integrin binding were incapable of promoting extravasation. P66 itself does not promote detectable microvascular interactions, suggesting that vascular adhesion of B. burgdorferi mediated by other adhesins, sets the stage for P66-integrin interactions leading to transmigration. Although integrin-binding proteins with diverse functions are encoded by a variety of bacterial pathogens, P66 is the first to have a documented and direct role in vascular transmigration. The emerging picture of vascular escape by the Lyme spirochete shows similarities, but distinct differences from leukocyte transmigration. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
42. Pharmacokinetics and Pharmacodynamics of Tissue Plasminogen Activator Administered Through an External Ventricular Drain.
- Author
-
Kramer, Andreas, Jenne, Craig, Holodinsky, Jessalyn, Todd, Stephanie, Roberts, Derek, Kubes, Paul, Zygun, David, Hill, Michael, Leger, Caroline, Wong, John, Kramer, Andreas H, Holodinsky, Jessalyn K, Roberts, Derek J, Zygun, David A, Hill, Michael D, and Wong, John H
- Subjects
TISSUE plasminogen activator ,PHARMACOKINETICS ,PHARMACODYNAMICS ,INTRAVENTRICULAR hemorrhage ,HEMORRHAGE complications ,CEREBROSPINAL fluid ,CEREBRAL ventricle surgery ,FIBRINOLYTIC agents ,CEREBRAL hemorrhage ,CEREBRAL ventricles ,COMPARATIVE studies ,INTRACRANIAL aneurysms ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,SUBARACHNOID hemorrhage ,PILOT projects ,EVALUATION research ,RANDOMIZED controlled trials ,TREATMENT effectiveness ,INTRAVENTRICULAR injections ,DISEASE complications - Abstract
Background: Intraventricular hemorrhage (IVH) frequently complicates spontaneous intracerebral or subarachnoid hemorrhage (SAH). Administration of intraventricular tissue plasminogen activator (TPA) accelerates blood clearance, but optimal dosing has not been clarified. Using a standardized TPA dose, we assessed peak cerebrospinal fluid (CSF) TPA concentrations, the rate at which TPA clears, and the relationship between TPA concentration and biological activity.Methods: Twelve patients with aneurysmal SAH and IVH, treated with endovascular coiling and ventricular drainage, were randomized to receive either 2 mg intraventricular TPA or placebo every 12 h (five doses). CT scans were performed 12, 48, and 72 h after initial administration, and blood was quantified using the SAH Sum and IVH Scores. CSF TPA and fibrin degradation product (D-dimer) concentrations were measured at baseline and 1, 6, and 12 h after the first dose using ELISA assays.Results: Median CSF TPA concentrations in seven TPA-treated patients were 525 (IQR 352-2129), 323 (233-413), and 47 (29-283) ng/ml, respectively, at 1, 6, and 12 h after drug administration. Peak concentrations varied markedly (401-8398 ng/ml). Two patients still had slightly elevated levels (283-285 ng/ml) when the second dose was due after 12 h. There was no significant correlation between the magnitude of CSF TPA elevation and the rate of blood clearance or degree of D-dimer elevation. D-dimer peaked at 6 h, had declined by 12 h, and correlated strongly with radiographic IVH clearance (r = 0.82, p = 0.02).Conclusions: The pharmacokinetics of intraventricular TPA administration varies between individual patients. TPA dose does not need to exceed 2 mg. The optimal administration interval is every 8-12 h. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
43. Imaging the dynamic platelet-neutrophil response in sterile liver injury and repair in mice.
- Author
-
Slaba, Ingrid, Wang, Jing, Kolaczkowska, Elzbieta, McDonald, Braedon, Lee, Woo‐Yong, and Kubes, Paul
- Published
- 2015
- Full Text
- View/download PDF
44. Bespoke brain immunity.
- Author
-
Nguyen, Rita H. and Kubes, Paul
- Published
- 2021
- Full Text
- View/download PDF
45. Intraventricular fibrinolysis with tissue plasminogen activator is associated with transient cerebrospinal fluid inflammation: a randomized controlled trial.
- Author
-
Kramer, Andreas H, Jenne, Craig N, Zygun, David A, Roberts, Derek J, Hill, Michael D, Holodinsky, Jessalyn K, Todd, Stephanie, Kubes, Paul, and Wong, John H
- Subjects
THROMBOLYTIC therapy ,FIBRINOLYSIS ,BLOOD coagulation ,IRRITATION (Pathology) ,CEREBRAL circulation ,BLOOD circulation ,BRAIN blood-vessels ,HEMODYNAMICS - Abstract
Locally administered tissue plasminogen activator (TPA) accelerates clearance of intraventricular hemorrhage (IVH), but its impact on neurologic outcomes remains unclear and preclinical research suggests it may have pro-inflammatory effects. We randomly allocated patients with ruptured cerebral aneurysms and IVH, treated with endovascular coiling and ventricular drainage, to receive either 2-mg intraventricular TPA or placebo every 12 hours. Cerebrospinal fluid (CSF) and serum cytokine and white blood cell (WBC) concentrations were measured before drug administration and daily for 72 hours. Cerebrospinal fluid D-dimer levels were assessed 6 and 12 hours after administration to quantify fibrinolysis. Six patients were randomized to each group. Patients treated with TPA developed higher CSF cytokine concentrations compared with placebo-treated patients (P<0.05 for tumor necrosis factor-α, interferon-γ, interleukin (IL)-1α, IL-1β, IL-2, IL-4, and IL-6), as well as higher CSF WBC counts (P=0.03). Differences were greatest after 24 hours and decreased over 48 to 72 hours. The magnitude of the inflammatory response was significantly associated with peak CSF D-dimer concentration and extent of IVH clearance. We conclude that intraventricular TPA administration produces a transient local inflammatory response, the severity of which is strongly associated with the degree of fibrinolysis, suggesting it may be induced by release of hematoma breakdown products, rather than the drug itself. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
46. Active Negative Pressure Peritoneal Therapy After Abbreviated Laparotomy.
- Author
-
Kirkpatrick, Andrew W., Roberts, Derek J., Faris, Peter D., Ball, Chad G., Kubes, Paul, Tiruta, Corina, Zhengwen Xiao, Holodinsky, Jessalyn K., McBeth, Paul B., Doig, Christopher J., and Jenne, Craig N.
- Published
- 2015
- Full Text
- View/download PDF
47. Allogeneic Bone Marrow Transplant from MRL/MpJ Super-Healer Mice Does Not Improve Articular Cartilage Repair in the C57Bl/6 Strain.
- Author
-
Leonard, Catherine A., Lee, Woo-Yong, Tailor, Pankaj, Salo, Paul T., Kubes, Paul, and Krawetz, Roman J.
- Subjects
BONE marrow transplantation ,HOMOGRAFTS ,ARTICULAR cartilage ,CARTILAGE regeneration ,PHENOTYPES ,LABORATORY mice - Abstract
Background: Articular cartilage has been the focus of multiple strategies to improve its regenerative/ repair capacity. The Murphy Roths Large (MRL/MpJ) “super-healer” mouse demonstrates an unusual enhanced regenerative capacity in many tissues and provides an opportunity to further study endogenous cartilage repair. The objective of this study was to test whether the super-healer phenotype could be transferred from MRL/MpJ to non-healer C57Bl/6 mice by allogeneic bone marrow transplant. Methodology: The healing of 2mm ear punches and full thickness cartilage defects was measured 4 and 8 weeks after injury in control C57Bl/6 and MRL/MpJ “super-healer” mice, and in radiation chimeras reconstituted with bone marrow from the other mouse strain. Healing was assessed using ear hole diameter measurement, a 14 point histological scoring scale for the cartilage defect and an adapted version of the Osteoarthritis Research Society International scale for assessment of osteoarthritis in mouse knee joints. Principal Findings: Normal and chimeric MRL mice showed significantly better healing of articular cartilage and ear wounds along with less severe signs of osteoarthritis after cartilage injury than the control strain. Contrary to our hypothesis, however, bone marrow transplant from MRL mice did not confer improved healing on the C57Bl/6 chimeras, either in regards to ear wound healing or cartilage repair. Conclusion and Significance: The elusive cellular basis for the MRL regenerative phenotype still requires additional study and may possibly be dependent on additional cell types external to the bone marrow. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
48. Platelets in inflammation and infection.
- Author
-
Jenne, Craig N. and Kubes, Paul
- Subjects
BLOOD platelets ,HEMOSTASIS ,LEUCOCYTES ,MEGAKARYOCYTES ,AUTOIMMUNE diseases ,INFLAMMATION - Abstract
Although platelets are traditionally recognized for their central role in hemostasis, many lines of research clearly demonstrate these rather ubiquitous blood components are potent immune modulators and effectors. Platelets have been shown to directly recognize, sequester and kill pathogens, to activated and recruit leukocytes to sites of infection and inflammation, and to modulate leukocyte behavior, enhancing their ability to phagocytose and kill pathogens and inducing unique effector functions, such as the production of Neutrophil Extracellular Traps (NETs). This multifaceted response to infection and inflammation is due, in part, to the huge array of soluble mediators and cell surface molecules expressed by platelets. From their earliest origins as primordial hemocytes in invertebrates to their current form as megakaryocyte-derived cytoplasts, platelets have evolved to be one of the key regulators of host intravascular immunity and inflammation. In this review, we present the diverse roles platelets play in immunity and inflammation associated with autoimmune diseases and infection. Additionally, we highlight recent advances in our understanding of platelet behavior made possible through the use of advanced imaging techniques that allow us to visualize platelets and their interactions, in real-time, within the intact blood vessels of a living host. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
49. Intravital imaging - dynamic insights into natural killer T cell biology.
- Author
-
Pei Xiong Liew and Kubes, Paul
- Subjects
CYTOTOXIC T cells ,CYTOLOGY ,LYMPHOCYTES ,IMMUNE response ,INFLAMMATION ,THYMUS - Abstract
Natural killer T (NKT) cells were first recognized more than two decades ago as a separate and distinct lymphocyte lineage that modulates an expansive range of immune responses. As innate immune cells, NKT cells are activated early during inflammation and infection, and can subsequently stimulate or suppress the ensuing immune response. As a result, researchers hope to harness the immunomodulatory properties of NKT cells to treat a variety of diseases. However, many questions still remain unanswered regarding the biology of NKT cells, including how these cells traffic from the thymus to peripheral organs and how they play such contrasting roles in different immune responses and diseases. In this new era of intravital fluorescence microscopy, we are now able to employ this powerful tool to provide quantitative and dynamic insights into NKT cell biology including cellular dynamics, patrolling, and immunoregulatory functions with exquisite resolution. This review will highlight and discuss recent studies that use intravital imaging to understand the spectrum of NKT cell behavior in a variety of animal models. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
50. Integration of metabolic and inflammatory mediator profiles as a potential prognostic approach for septic shock in the intensive care unit.
- Author
-
Mickiewicz, Beata, Tam, Patrick, Jenne, Craig N., Leger, Caroline, Wong, Josee, Winston, Brent W., Doig, Christopher, Kubes, Paul, and Vogel, Hans J.
- Published
- 2015
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.