Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice
| Autor: | Silvio Antoniak, Meagan D. Bridges, Eric Camerer, Stephanie A. Montgomery, Stephen D. Miles, Melinda A. Beck, Lauryn R. Tumey, David R. Martinez, Nigel Mackman, Randall C. Gunther, Clare M. Schmedes, Kohei Tatsumi, Vanthana Bharathi |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Pathology medicine.medical_specialty Myeloid F2rl1 Neutrophils Immunology macrophage protease-activated receptor 2 (PAR2) Proinflammatory cytokine Mice Immune system Orthomyxoviridae Infections medicine Animals Receptor PAR-2 influenza A virus Immunology and Allergy Myeloid Cells toll-like receptor 3 Receptor Lung Protease-activated receptor 2 Original Research Innate immune system medicine.diagnostic_test Chemistry Interferon-beta RC581-607 Mice Inbred C57BL medicine.anatomical_structure Bronchoalveolar lavage TLR3 innate immune response Cytokines Female Immunologic diseases. Allergy lung epithelial cell |
| Zdroj: | Frontiers in Immunology, Vol 12 (2021) Frontiers in Immunology |
| ISSN: | 1664-3224 |
| DOI: | 10.3389/fimmu.2021.791017 |
| Popis: | BackgroundInnate immune responses to influenza A virus (IAV) infection are initiated in part by toll-like receptor 3 (TLR3). TLR3-dependent signaling induces an antiviral immune response and an NFκB-dependent inflammatory response. Protease-activated receptor 2 (PAR2) inhibits the antiviral response and enhances the inflammatory response. PAR2 deficiency protected mice during IAV infection. However, the PAR2 expressing cell-types contributing to IAV pathology in mice and the mechanism by which PAR2 contributes to IAV infection is unknown.MethodsIAV infection was analyzed in global (Par2-/-), myeloid (Par2fl/fl;LysMCre+) and lung epithelial cell (EpC) Par2 deficient (Par2fl/fl;SPCCre+) mice and their respective controls (Par2+/+ and Par2fl/fl). In addition, the effect of PAR2 activation on polyinosinic-polycytidylic acid (poly I:C) activation of TLR3 was analyzed in bone marrow-derived macrophages (BMDM). Lastly, we determined the effect of PAR2 inhibition in wild-type (WT) mice.ResultsAfter IAV infection, Par2-/- and mice with myeloid Par2 deficiency exhibited increased survival compared to infected controls. The improved survival was associated with reduced proinflammatory mediators and reduced cellular infiltration in bronchoalveolar lavage fluid (BALF) of Par2-/- and Par2fl/fl;LysMCre+ 3 days post infection (dpi) compared to infected control mice. Interestingly, Par2fl/fl;SPCCre+ mice showed no survival benefit compared to Par2fl/fl. In vitro studies showed that Par2-/- BMDM produced less IL6 and IL12p40 than Par2+/+ BMDM after poly I:C stimulation. In addition, activation of PAR2 on Par2+/+ BMDM increased poly I:C induction of IL6 and IL12p40 compared to poly I:C stimulation alone. Importantly, PAR2 inhibition prior to IAV infection protect WT mice.ConclusionGlobal Par2 or myeloid cell but not lung EpC Par2 deficiency was associated with reduced BALF inflammatory markers and reduced IAV-induced mortality. Our study suggests that PAR2 may be a therapeutic target to reduce IAV pathology. |
| Databáze: | OpenAIRE |
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