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PAR2-Mediated cAMP Generation Suppresses TRPV4-Dependent Ca2+ Signaling in Alveolar Macrophages to Resolve TLR4-Induced Inflammation
- Source :
- Cell Reports, Vol 27, Iss 3, Pp 793-805.e4 (2019)
- Publication Year :
- 2019
- Publisher :
- Elsevier, 2019.
-
Abstract
- Summary: 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. : 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. Keywords: protease-activating receptor 2, alveolar macrophages, cAMP, TRPV4, NFAT, acute lung injury, Ca2+ entry
- Subjects :
- 0301 basic medicine
TRPV4
Chemistry
Inflammation
NFAT
Lung injury
respiratory system
General Biochemistry, Genetics and Molecular Biology
Cell biology
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Thrombin
lcsh:Biology (General)
TLR4
medicine
medicine.symptom
Receptor
Transcription factor
lcsh:QH301-705.5
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 22111247
- Volume :
- 27
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Cell Reports
- Accession number :
- edsair.doi.dedup.....3769a188f17ca2c041c873448f40c08a