Parsing the IL-37-Mediated Suppression of Inflammasome Function

Abstract

Interleukin (IL)-37 is a member of the IL-1 family of cytokines. Although its broad anti-inflammatory properties are well described, the effects of IL-37 on inflammasome function remain poorly understood. Performing gene expression analyses, ASC oligomerization/speck assays and caspase-1 assays in bone marrow-derived macrophages (BMDM), and employing an in vivo endotoxemia model, we studied how IL-37 affects the expression and maturation of IL-1β and IL-18, inflammasome activation, and pyroptosis in detail. IL-37 inhibited IL-1β production by NLRP3 and AIM2 inflammasomes, and IL-18 production by the NLRP3 inflammasome. This inhibition was partially attributable to effects on gene expression: whereas IL-37 did not affect lipopolysaccharide (LPS)-induced mRNA expression of Il18 or inflammasome components, IL-37-transgenic BMDM displayed an up to 83% inhibition of baseline and LPS-stimulated Il1b compared to their wild-type counterparts. Importantly, we observed that IL-37 suppresses nigericin- and silica-induced ASC oligomerization/speck formation (a step in inflammasome activation and subsequent caspase-1 activation), and pyroptosis (−50%). In mice subjected to endotoxemia, IL-37 inhibited plasma IL-1β (−78% compared to wild-type animals) and IL-18 (−61%). Thus, our study adds suppression of inflammasome activity to the portfolio of anti-inflammatory pathways employed by IL-37, highlighting this cytokine as a potential tool for treating inflammasome-driven diseases.

Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities

“…Consistent with the known functions of IL-37 21,22,65,[69][70][71][72] , IL-37tg pups were nearly completely protected from the NECdriven increases in IL-1β, IL-6, TNF, and IL-17F, and from the reduction in TGF-β 1 . Contrary to expectations, IL-37 had little effect on type 1 mediators such as IL-12 and IL-23, the distribution of ILC subsets, nor on IL-10 in NEC.…”

IL-37 Gene Modification Enhances the Protective Effects of Mesenchymal Stromal Cells on Intestinal Ischemia Reperfusion Injury

“…In addition, IL-37 in vivo could inhibit NLRP3 activation also be mentioned in colitis and LPS-induced disease [19,22,[35][36][37]. In recent study, Rudloff et al reported that IL-37 significantly suppress inflammasome activity in vivo to ameliorate inflammasome-driven diseases, which could corroborate our study results to some extent [38].…”

IL-37 Gene Modification Enhances the Protective Effects of Mesenchymal Stromal Cells on Intestinal Ischemia Reperfusion Injury

“…In addition, IL-37 in vivo could inhibit NLRP3 activation also in colitis- and LPS-induced disease [ 19 , 22 , 35 – 37 ]. In a recent study, Rudloff et al reported that IL-37 significantly suppresses inflammasome activity in vivo to ameliorate inflammasome-driven diseases, which could corroborate our study results to some extent [ 38 ].…”