Background: Par2 has been shown to modulate the TLR3 pathway by inhibiting innate antiviral immune responses while increasing inflammation. Importantly, PAR2 deficiency was associated with protection of mice during RNA virus infection, including CVB3 myocarditis and influenza A virus infection (IAV).

Aims: To identify the PAR2 expressing cell-type contributing to IAV pathology in mice.

Methods: Global knockout (Par2^-/-) and myeloid (Par2^fl/fl;LysM^Cre+) Par2 deficient mice and controls (Par2^+/+ and Par2^fl/fl) were infected with IAV and assessed for weight loss and mortality. Proinflammatory mediators and cellularity in the bronchoalveolar lavage fluid (BALF) was measured 3 days post infection (dpi). In addition, PAR2-dependent modulation of polyI:C activation of TLR3 were analyzed in bone marrow-derived macrophages (BMDM).

Results: After IAV infection, Par2^-/- mice exhibited increased survival compared to Par2^+/+ (Figure 1A). This was associated with reduced proinflammatory mediators (Figure 1B) and reduced neutrophils (Figure 1C) in the bronchial alveolar lavage fluid (BALF) of Par2^-/- 3dpi compared to infected Par2^+/+ mice. Importantly mice lacking myeloid PAR2 (Par2^fl/fl;LysM^Cre+) exhibited improved survival after IAV infection compared to Par2^fl/fl mice (Figure 2A). As seen in Par2^-/- mice, Par2^fl/fl;LysM^Cre+ mice had reduced proinflammatory mediators (Figure 2B) and reduced neutrophils (Figure 2C) in BALF 3dpi. In vitro studies showed that Par2^-/- BMDM produced less IL-6 and IL-12p40 than Par2^+/+ BMDM 24hrs after polyIC stimulation (Figure 2D). In addition, activation of PAR2 on wild-type BMDM during polyIC stimulation increased IL-6 and IL-12 release compared to polyIC stimulation alone (Figure 2D).

Figure 1: Gobal Par2 deficiency during IAV infection
​Figure 2: Myeloid Par2 deficiency during IAV infection

Conclusions: Global Par2 or myeloid cell Par2 deficiency protects mice from IAV-induced mortality. The improved survival was associated with reduced proinflammatory cytokine levels and neutrophils in BALF. PAR2 stimulation enhances cytokine release from polyIC stimulated BMDM. Our data suggest that PAR2 inhibition could be a therapeutic approach to reduce IAV pathology by reducing lung inflammation.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/myeloid-par2-deficiency-protects-mice-during-iav-infection/