Chemerin aggravates DSS-induced colitis by suppressing M2 macrophage polarization

Abstract

Chemerin is present in various inflammatory sites and is closely involved in tissue inflammation. Recent studies have demonstrated that chemerin treatment can cause either anti-inflammatory or pro-inflammatory effects according to the disease model being investigated. Elevated circulating chemerin was recently found in patients with inflammatory bowel disease (IBD); however, the role of chemerin in intestinal inflammation remains unknown. In this study, we demonstrated that the administration of exogenous chemerin (aa17–156) aggravated the severity of dextran sulfate sodium (DSS)-induced colitis, which was characterized by higher clinical scores, extensive mucosal damage and significantly increased local and systemic production of pro-inflammatory cytokines, including IL-6, TNF-α and interferon (IFN-γ). Interestingly, chemerin did not appear to influence the magnitudes of inflammatory infiltrates in the colons, but did result in significantly decreased colonic expression of M2 macrophage-associated genes, including Arginase 1 (Arg-1), Ym1, FIZZ1 and IL-10, following DSS exposure, suggesting an impaired M2 macrophage skewing in vivo. Furthermore, an in vitro experiment showed that the addition of chemerin directly suppressed M2 macrophage-associated gene expression and STAT6 phosphorylation in IL-4-stimulated macrophages. Significantly elevated chemerin levels were found in colons from DSS-exposed mice and from ulcerative colitis (UC) patients and appeared to positively correlate with disease severity. Moreover, the in vivo administration of neutralizing anti-chemerin antibody significantly improved intestinal inflammation following DSS exposure. Taken together, our findings reveal a pro-inflammatory role for chemerin in DSS-induced colitis and the ability of chemerin to suppress the anti-inflammatory M2 macrophage response. Our study also suggests that upregulated chemerin in inflamed colons may contribute to the pathogenesis of IBD.

Chemerin, a novel player in inflammatory bowel disease

“…9 In vitro experiments using peritoneal macrophages demonstrate that (i) chemerin alone has no effect on the expression of the M2 genes analyzed; (ii) chemerin does not enhance lipopolysaccharidemediated M1 activation, in agreement with recently published findings; 10 (iii) chemerin impairs IL-4-induced phosphorylation of STAT6 and M2-induced macrophage polarization; and (iv) IL-4 upregulates expression of CMKLR1 by macrophages.…”

“…9 Administration of this antibody improves histological scores, but not the clinical manifestations of DSS colitis. Lin and colleagues 9 speculate that this approach does not efficiently block endogenous chemerin and suggest the use of chemerin knockout mice to perform confirmatory experiments.…”

“…In this model, mucosal inflammation is maintained by cells of the innate immune system. 8 Using this model, Lin and colleagues 9 report that chemerin aggravates colitis. Importantly, intraperitoneal injection of chemerin (aa16-157) strongly increases chemerin serum levels, but does not cause inflammation in healthy mice.…”

“…The immune-suppressive cytokines TGF-beta 12 and IL-4 induce CMKLR1 expression. 9 Thus, further studies are needed to elucidate whether classically activated macrophages are less responsive to chemerin compared to alternatively activated cells.…”

“…6 In colon biopsies of patients with ulcerative colitis, the expression of chemerin is higher in inflamed tissues and, importantly, is further increased in more severely inflamed tissues. 9 Colon cells isolated from DSS-treated mice release chemerin at levels consistent with disease severity. Therefore, only locally produced chemerin is associated with disease severity in rodent and human IBD.…”