Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice

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...

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Autores principales:	Randall C. Gunther, Vanthana Bharathi, Stephen D. Miles, Lauryn R. Tumey, Clare M. Schmedes, Kohei Tatsumi, Meagan D. Bridges, David Martinez, Stephanie A. Montgomery, Melinda A. Beck, Eric Camerer, Nigel Mackman, Silvio Antoniak
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	toll-like receptor 3 influenza A virus innate immune response macrophage lung epithelial cell protease-activated receptor 2 (PAR2) Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/9ce01fde26334c13975a5e0be80b3539
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spelling	oai:doaj.org-article:9ce01fde26334c13975a5e0be80b35392021-12-01T23:50:38ZMyeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice1664-322410.3389/fimmu.2021.791017https://doaj.org/article/9ce01fde26334c13975a5e0be80b35392021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.791017/fullhttps://doaj.org/toc/1664-3224BackgroundInnate 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.Randall C. GuntherVanthana BharathiStephen D. MilesLauryn R. TumeyClare M. SchmedesKohei TatsumiMeagan D. BridgesDavid MartinezStephanie A. MontgomeryMelinda A. BeckEric CamererNigel MackmanSilvio AntoniakFrontiers Media S.A.articletoll-like receptor 3influenza A virusinnate immune responsemacrophagelung epithelial cellprotease-activated receptor 2 (PAR2)Immunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	toll-like receptor 3 influenza A virus innate immune response macrophage lung epithelial cell protease-activated receptor 2 (PAR2) Immunologic diseases. Allergy RC581-607
spellingShingle	toll-like receptor 3 influenza A virus innate immune response macrophage lung epithelial cell protease-activated receptor 2 (PAR2) Immunologic diseases. Allergy RC581-607 Randall C. Gunther Vanthana Bharathi Stephen D. Miles Lauryn R. Tumey Clare M. Schmedes Kohei Tatsumi Meagan D. Bridges David Martinez Stephanie A. Montgomery Melinda A. Beck Eric Camerer Nigel Mackman Silvio Antoniak Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice
description	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.
format	article
author	Randall C. Gunther Vanthana Bharathi Stephen D. Miles Lauryn R. Tumey Clare M. Schmedes Kohei Tatsumi Meagan D. Bridges David Martinez Stephanie A. Montgomery Melinda A. Beck Eric Camerer Nigel Mackman Silvio Antoniak
author_facet	Randall C. Gunther Vanthana Bharathi Stephen D. Miles Lauryn R. Tumey Clare M. Schmedes Kohei Tatsumi Meagan D. Bridges David Martinez Stephanie A. Montgomery Melinda A. Beck Eric Camerer Nigel Mackman Silvio Antoniak
author_sort	Randall C. Gunther
title	Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice
title_short	Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice
title_full	Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice
title_fullStr	Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice
title_full_unstemmed	Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice
title_sort	myeloid protease-activated receptor-2 contributes to influenza a virus pathology in mice
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/9ce01fde26334c13975a5e0be80b3539
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Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice

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