PAR1 regulation of CXCL1 expression and neutrophil recruitment to the lung in mice infected with influenza A virus

Antoniak, Silvio; Tatsumi, Kohei; Schmedes, Clare M.; Egnatz, Grant J.; Auriemma, Alyson C.; Bharathi, Vanthana; Stokol, Tracy; Beck, Melinda A.; Griffin, John H.; Palumbo, Joseph S.; Mackman, Nigel

doi:10.1111/jth.15221

Cited by 12 publications

(16 citation statements)

References 39 publications

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“…In contrast, PAR1 reduces TLR3-NFkB inflammation but enhances TLR3-IFNb responses (Figure 12) (8,23,36,43,48). In line with this proposed receptor interaction, we have recently shown that the absence of PAR1 leads to increased proinflammatory CXCL1 expression and increased BALF neutrophil numbers which were associated with higher mortality compared to WT mice (26).…”

Section: Discussionmentioning

confidence: 63%

“…Cellspecific PAR2 deficient mice were generated by crossing female Par2 fl/fl with male Par2 fl/fl mice expressing Cre recombinase in a cell type-specific manner. To generate mice with Par2 deleted in lung EpCs we used the surfactant protein C (SPC) promoter (Par2 fl/fl ;SPC Cre+ mice) (26,27). The Par2 gene was deleted in the myeloid lineage (monocytes/macrophages and neutrophils) using the lysosomal M (LysM) promoter (Par2 fl/fl ;LysM Cre+ ) (26,(28)(29)(30)(31).…”

Section: Micementioning

confidence: 99%

“…To generate mice with Par2 deleted in lung EpCs we used the surfactant protein C (SPC) promoter (Par2 fl/fl ;SPC Cre+ mice) (26,27). The Par2 gene was deleted in the myeloid lineage (monocytes/macrophages and neutrophils) using the lysosomal M (LysM) promoter (Par2 fl/fl ;LysM Cre+ ) (26,(28)(29)(30)(31). For mice with cell type-specific Par2 deletion, littermate Par2 fl/fl mice were used as controls.…”

Section: Micementioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 63%

Section: Micementioning

confidence: 99%

Section: Micementioning

confidence: 99%

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

et al. 2021

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“…To delete PAR1 in CFs (PAR1ΔCF), we used mice expressing Cre recombinase under the transcription factor 21 (TCF21) obtained from Dr. Tallquist 34 . Female PAR1 fl/fl mice 35 , 36 were crossed with male Cre-expressing mice to generate PAR1 fl/fl ;Mlc2v Cre and PAR1 fl/fl ;TCF21 Cre-ERT2 . To activate TCF21 Cre-ERT2 expression 34 , 37 in PAR1 fl/fl ;TCF21 Cre-ERT2 mice, 6 week old mice were gavaged with 2 mg of tamoxifen (Sigma-Aldrich, St. Louis, MO, USA) for 5 consecutive days and then mice used 5 days later.…”

Section: Methodsmentioning

confidence: 99%

“…Variations in input RNA levels and reaction efficiency was corrected against 18S rRNA (4310893E, Applied Biosystems). All RT-PCR reactions were performed with the SSoFast Advanced Universal Supermix in a Bio-Rad cycler (Bio-Rad Laboratories, Hercules, CA, USA) as described elsewhere 36 , 41 .…”

Section: Methodsmentioning

confidence: 99%

Cell type-specific roles of PAR1 in Coxsackievirus B3 infection

Bode

Schmedes

Egnatz

et al. 2021

Sci Rep

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Protease-activated receptor 1 (PAR1) is widely expressed in humans and mice, and is activated by a variety of proteases, including thrombin. Recently, we showed that PAR1 contributes to the innate immune response to viral infection. Mice with a global deficiency of PAR1 expressed lower levels of CXCL10 and had increased Coxsackievirus B3 (CVB3)-induced myocarditis compared with control mice. In this study, we determined the effect of cell type-specific deletion of PAR1 in cardiac myocytes (CMs) and cardiac fibroblasts (CFs) on CVB3-induced myocarditis. Mice lacking PAR1 in either CMs or CFs exhibited increased CVB3 genomes, inflammatory infiltrates, macrophages and inflammatory mediators in the heart and increased CVB3-induced myocarditis compared with wild-type controls. Interestingly, PAR1 enhanced poly I:C induction of CXCL10 in rat CFs but not in rat neonatal CMs. Importantly, activation of PAR1 reduced CVB3 replication in murine embryonic fibroblasts and murine embryonic cardiac myocytes. In addition, we showed that PAR1 reduced autophagy in murine embryonic fibroblasts and rat H9c2 cells, which may explain how PAR1 reduces CVB3 replication. These data suggest that PAR1 on CFs protects against CVB3-induced myocarditis by enhancing the anti-viral response whereas PAR1 on both CMs and fibroblasts inhibits viral replication.

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Interaction among inflammasome, PANoptosise, and innate immune cells in infection of influenza virus: Updated review

Wei,

Wang,

Zhou

2023

Immunity Inflam & Disease

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BackgroundInfluenza virus (IV) is a leading cause of respiratory tract infections, eliciting responses from key innate immune cells such as Macrophages (MQs), Neutrophils, and Dendritic Cells (DCs). These cells employ diverse mechanisms to combat IV, with Inflammasomes playing a pivotal role in viral infection control. Cellular death mechanisms, including Pyroptosis, Apoptosis, and Necroptosis (collectively called PANoptosis), significantly contribute to the innate immune response.MethodsIn this updated review, we delve into the intricate relationship between PANoptosis and Inflammasomes within innate immune cells (MQs, Neutrophils, and DCs) during IV infections. We explore the strategies employed by IV to evade these immune defenses and the consequences of unchecked PANoptosis and inflammasome activation, including the potential development of severe complications such as cytokine storms and tissue damage.ResultsOur analysis underscores the interplay between PANoptosis and Inflammasomes as a critical aspect of the innate immune response against IV. We provide insights into IV's various mechanisms to subvert these immune pathways and highlight the importance of understanding these interactions to develop effective antiviral medications.ConclusionA comprehensive understanding of the dynamic interactions between PANoptosis, Inflammasomes, and IV is essential for advancing our knowledge of innate immune responses to viral infections. This knowledge will be invaluable in developing targeted antiviral therapies to combat IV and mitigate potential complications, including cytokine storms and tissue damage.

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PAR1 regulation of CXCL1 expression and neutrophil recruitment to the lung in mice infected with influenza A virus

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 12 publications

References 39 publications

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

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

Cell type-specific roles of PAR1 in Coxsackievirus B3 infection

Interaction among inflammasome, PANoptosise, and innate immune cells in infection of influenza virus: Updated review

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