PAR2-Mediated cAMP Generation Suppresses TRPV4-Dependent Ca2+ Signaling in Alveolar Macrophages to Resolve TLR4-Induced Inflammation.

Alveolar macrophages (AMs), upon sensing pathogens, trigger host defense by activating toll-like receptor 4 (TLR4), but the counterbalancing mechanisms that deactivate AM inflammatory signaling and prevent lethal edema, the hallmark of acute lung injury (ALI), remain unknown. Here, we demonstrate the essential role of AM protease-activating receptor 2 (PAR2) in rapidly suppressing inflammation to prevent long-lasting injury. We show that thrombin, released during TLR4-induced lung injury, directly activates PAR2 to generate cAMP, which abolishes Ca²⁺ entry through the TRPV4 channel. Deletion of PAR2 and thus the accompanying cAMP generation augments Ca²⁺ entry via TRPV4, causing sustained activation of the transcription factor NFAT to produce long-lasting TLR4-mediated inflammatory lung injury. Rescuing thrombin-sensitive PAR2 expression or blocking TRPV4 activity in PAR2-null AMs restores their capacity to resolve inflammation and reverse lung injury. Thus, activation of the thrombin-induced PAR2-cAMP cascade in AMs suppresses TLR4 inflammatory signaling to reinstate tissue integrity. • Post-injury, thrombin activation of AM PAR2 suppresses TLR4-mediated inflammation • PAR2-generated cAMP abolishes Ca²⁺ entry through TRPV4 • Ca²⁺ entry causes NFAT-dependent long-lasting inflammatory signaling in Par2 ^−/− AMs • Rescuing thrombin-sensitive PAR2 or TRPV4 blockade in Par2 ^−/− AMs resolves injury Alveolar macrophages trigger inflammatory signaling upon TLR4 activation by pathogens, and this signaling, if unchecked, can lead to pulmonary edema, the hallmark of acute lung injury. Rayees et al. demonstrate that thrombin ligation of the alveolar macrophage protease-activating receptor 2 post-injury suppresses inflammatory lung injury via a cAMP blockade of the TRPV4 channel. [ABSTRACT FROM AUTHOR]