CXCL1 and CXCL2 Regulate NLRP3 Inflammasome Activation via G-Protein-Coupled Receptor CXCR2

Boro, Monoranjan and Balaji, Kithiganahalli Narayanaswamy (2017) CXCL1 and CXCL2 Regulate NLRP3 Inflammasome Activation via G-Protein-Coupled Receptor CXCR2. In: JOURNAL OF IMMUNOLOGY, 199 (5). pp. 1660-1671.

PDF Jou_Imm_199-5_1660_2017.pdf - Published Version Restricted to Registered users only Download (2MB) | Request a copy

Abstract

Inflammation is an extensively concerted process that confers protection to the host encountering immune insult. The major inflammatory mediators include IL-1 family members, such as IL-1 beta, and the functional activation of such molecules is arbitrated by their regulated cleavage brought about by components of a multiprotein complex called inflammasome. In this context, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation often acts as a rate-limiting step in regulating critical cell-fate decisions in various inflammatory scenarios. In this study, we identify the G-protein-coupled receptor CXCR2 (recognizing chemokines CXCL1 and CXCL2) as another arm feeding into the regulated activation of NLRP3 inflammasome in macrophages. We demonstrate that in vivo blocking of CXCL1 and CXCL2 can significantly reduce the Mycobacterium tuberculosis-induced bioactive IL-1 beta production. Further, CXCL1 could amplify the inflammasome activation in in vivo mouse models of carrageenan-induced inflammation in footpads and air pouches. The mechanistic insights revealed CXCR2-driven protein kinase C mu-dependent integrin-linked kinase to be essential for CXCL1-mediated activation of NLRP3 inflammasome. Blocking the activity of integrin-linked kinase or protein kinase C mu either by small interfering RNA-mediated knockdown or pharmacological inhibitor compromised inflammasome activation and subsequent production of bioactive IL-1 beta. Taken together, our study demonstrates CXCR2-driven activation of NLRP3 inflammasome in macrophages and indicates a potential host-directed therapeutic target to limit the damaging inflammation associated with overt production of proinflammatory IL-1 beta.

Item Type:	Journal Article
Publication:	JOURNAL OF IMMUNOLOGY
Additional Information:	Copy right for this article belongs to the AMER ASSOC IMMUNOLOGISTS, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	16 Sep 2017 06:24
Last Modified:	16 Sep 2017 06:24
URI:	http://eprints.iisc.ac.in/id/eprint/57795

Actions (login required)

View Item