Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4.
Journal Article (Journal Article)
Serine proteases such as trypsin and mast cell tryptase cleave protease-activated receptor-2 (PAR2) at R(36)↓S(37) and reveal a tethered ligand that excites nociceptors, causing neurogenic inflammation and pain. Whether proteases that cleave PAR2 at distinct sites are biased agonists that also induce inflammation and pain is unexplored. Cathepsin S (Cat-S) is a lysosomal cysteine protease of antigen-presenting cells that is secreted during inflammation and which retains activity at extracellular pH. We observed that Cat-S cleaved PAR2 at E(56)↓T(57), which removed the canonical tethered ligand and prevented trypsin activation. In HEK and KNRK cell lines and in nociceptive neurons of mouse dorsal root ganglia, Cat-S and a decapeptide mimicking the Cat-S-revealed tethered ligand-stimulated PAR2 coupling to Gαs and formation of cAMP. In contrast to trypsin, Cat-S did not mobilize intracellular Ca(2+), activate ERK1/2, recruit β-arrestins, or induce PAR2 endocytosis. Cat-S caused PAR2-dependent activation of transient receptor potential vanilloid 4 (TRPV4) in Xenopus laevis oocytes, HEK cells and nociceptive neurons, and stimulated neuronal hyperexcitability by adenylyl cyclase and protein kinase A-dependent mechanisms. Intraplantar injection of Cat-S caused inflammation and hyperalgesia in mice that was attenuated by PAR2 or TRPV4 deletion and adenylyl cyclase inhibition. Cat-S and PAR2 antagonists suppressed formalin-induced inflammation and pain, which implicates endogenous Cat-S and PAR2 in inflammatory pain. Our results identify Cat-S as a biased agonist of PAR2 that causes PAR2- and TRPV4-dependent inflammation and pain. They expand the role of PAR2 as a mediator of protease-driven inflammatory pain.
Full Text
Duke Authors
Cited Authors
- Zhao, P; Lieu, T; Barlow, N; Metcalf, M; Veldhuis, NA; Jensen, DD; Kocan, M; Sostegni, S; Haerteis, S; Baraznenok, V; Henderson, I; Lindström, E; Guerrero-Alba, R; Valdez-Morales, EE; Liedtke, W; McIntyre, P; Vanner, SJ; Korbmacher, C; Bunnett, NW
Published Date
- September 26, 2014
Published In
Volume / Issue
- 289 / 39
Start / End Page
- 27215 - 27234
PubMed ID
- 25118282
Pubmed Central ID
- PMC4175355
Electronic International Standard Serial Number (EISSN)
- 1083-351X
Digital Object Identifier (DOI)
- 10.1074/jbc.M114.599712
Language
- eng
Conference Location
- United States