Chemerin, a Novel Player in Inflammatory Bowel Disease

LETTER TO EDITOR

Chemerin, a novel player in inflammatory bowel disease

C Buechler

Cellular & Molecular Immunology (2014) 11, 315–316; doi:10.1038/cmi.2014.14; published online 7 April 2014

nflammatory bowel disease (IBD) Mesenteric fat hypertrophy is a com- loss, colon shortening, and exaggerated I manifests during Crohn’s disease mon feature in IBD, particularly in histological damage, as well as a higher and ulcerative colitis as well as in a group Crohn’s disease.3 Proteins secreted by disease activity index at day 8 following of inflammatory disorders of the gastro- adipose tissue, such as adiponectin and DSS exposure. TNF and IL-6 serum levels intestinal tract.1 The etiology of IBD is leptin, regulate immune function, sug- and secretion by colonic cells are mar- thought to be a combination of genetics gesting that increased synthesis of these kedly induced (Figure 1). Unexpectedly, and environmental factors, including the proteins in adipose tissue and higher sys- chemerin administration does not affect microbiome and immune system of the temic levels in IBD may contribute to the number of dendritic cells, neutrophils, individual.1 disease pathogenesis.3 Chemerin, which macrophages and natural killer cells in The initial immune response in the is mainly expressed in adipocytes and the colon. RT-PCR expression analysis intestine is controlled by macrophages, hepatocytes, is also present at higher reveals a colitis-associated mRNA upregula- dendritic cells and intestinal epithelial concentrations in serum from IBD tion of the M2 genes, including arginase-1 cells. Intestinal macrophages are pha- patients.4–6 Chemerin is an attractant and IL-10, which is completely abrogated gocytic and bactericidal, but are mostly for immune cells and may play a role in by chemerin treatment (Figure 1). refractory to inflammatory stimulation. the recruitment of tissue macrophages.4 The chemerin receptor CMKLR1 is Microbes do not trigger the production Chemerin produced by human fetal expressed by macrophages, but not neu- of pro-inflammatory cytokines, prevent- intestinal epithelial cells constitutes most trophils or dendritic cells, suggesting that ing an unfavorable response to resident of the chemotactic macrophage activity this chemokine may directly affect commensal flora. These cells do not observed in cultured fetal intestinal epi- macrophages function.9 In vitro experi- 7 respond to Toll-like receptor ligands and thelial cells. In mature intestine, small ments using peritoneal macrophages express anti-inflammatory cytokines. In amounts of chemerin are expressed, sug- demonstrate that (i) chemerin alone IBD, Toll-like receptor-responsive macro- gesting that the postnatal attraction of has no effect on the expression of phages that release pro-inflammatory immune cells is initiated by other che- the M2 genes analyzed; (ii) chemerin 7 cytokines arise.2 Activated macrophages mokines. does not enhance lipopolysaccharide- are commonly categorized as classically Research on IBD commonly uses dex- mediated M1 activation, in agreement 10 activated (M1-type) or alternatively acti- tran sodium sulfate (DSS)-induced colitis with recently published findings; (iii) vated (M2-type). The latter are characteri- in mice. Intestinal hyperpermeability chemerin impairs IL-4-induced phos- zed by the expression of arginase and the affects the penetration of pathogens, toxic phorylation of STAT6 and M2-induced mannose receptor CD206.2 However, due compounds and macromolecules. In this macrophage polarization; and (iv) IL-4 to the heterogeneity of tissue macro- model, mucosal inflammation is main- upregulates expression of CMKLR1 by phages, this categorization is simplified, tained by cells of the innate immune macrophages. 8 and resident intestinal macrophages can- system. Using this model, Lin and collea- In mouse peritoneal macrophages, lipo- 9 11 not be easily assigned to one of these gues report that chemerin aggravates polysaccharide upregulates CMKLR1, classes.2 colitis. Importantly, intraperitoneal injec- whereas a second study demonstrates that tion of chemerin (aa16-157) strongly macrophage CMKLR1 is suppressed by increases chemerin serum levels, but does inflammatory cytokines and Toll-like Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany not cause inflammation in healthy mice. receptor ligands, such as lipopolysaccha- Correspondence: Dr C Buechler, Department of Circulating chemerin is elevated in ride. The immune-suppressive cytokines Internal Medicine I, Regensburg University experimental colitis (Figure 1) and is fur- TGF-beta12 and IL-4 induce CMKLR1 Hospital, D-93042 Regensburg, Germany. 9 E-mail: [email protected] ther increased by intraperitoneal admin- expression. Thus, further studies are Received: 10 February 2014; Accepted: 11 istration of chemerin. Chemerin-treated needed to elucidate whether classically February 2014 mice display significantly greater weight activated macrophages are less responsive Letter to Editor 316

ACKNOWLEDGEMENTS Bacteria Lumen Professor Dr Charalampos Aslanidis is acknowledged for helpful discussions and Dr Epithelial cells Claudia Kunst is acknowledged for providing Lamina propria the template to prepare the figure. M2 polarization Chemerin Macrophages

TNF 1 Cho JH. The genetics and immunopatho- IL-6 genesis of inflammatory bowel disease. Circulation Nat Rev Immunol 2008; 8: 458–466. Chemerin ? 2 Bain CC, Mowat AM. Intestinal macrophages— specialised adaptation to a unique TNF environment. Eur J Immunol 2011; 41: IL-6 Peripheral tissues 2494–2498. 3 Kaser A, Tilg H. ‘‘Metabolic aspects’’ in Adipocytes Hepatocytes inflammatory bowel diseases. Curr Drug Deliv 2012; 9: 326–332. Figure 1 Role of chemerin in dextran sodium sulfate (DSS) colitis. In DSS colitis, colonic epi- 4 Ernst MC, Sinal CJ. Chemerin: at the thelial cells release more chemerin. Chemerin enhances IL-6 and TNF secretion in these cells. It crossroads of inflammation and obesity. further blocks M2 polarization of macrophages, which is most likely associated with higher Trends Endocrinol Metab 2010; 21: 660– release of inflammatory cytokines. Increased pro-inflammatory cytokines in circulation might 667. induce chemerin in mesenteric adipocytes and subsequently contribute to higher systemic 5 Krautbauer S, Wanninger J, Eisinger K, levels. Whether chemerin in serum plays a role in the local effects in the bowel requires further Hader Y, Beck M, Kopp A et al. Chemerin study. Hepatocyte chemerin synthesis is not induced by inflammatory cytokines or lipopolysac- is highly expressed in hepatocytes and is induced in non-alcoholic steatohepatitis charide, suggesting that liver chemerin is not increased in inflammatory bowel disease. liver. Exp Mol Pathol 2013; 95: 199–205. 6 Weigert J, Obermeier F, Neumeier M, to chemerin compared to alternatively DSS-treated mice release chemerin at Wanninger J, Filarsky M, Bauer S et al. Circulating levels of chemerin and adipo- activated cells. levels consistent with disease severity. nectin are higher in ulcerative colitis and To evaluate the contribution of endo- Therefore, only locally produced chemerin chemerin is elevated in Crohn’s disease. genous chemerin to disease severity, an is associated with disease severity in rodent Inflamm Bowel Dis 2010; 16: 630–637. antibody blocking chemerin activity has and human IBD.6,9 7 Maheshwari A, Kurundkar AR, Shaik SS, 9 Kelly DR, Hartman Y, Zhang W et al. been tested. Administration of this anti- Higher circulating chemerin levels Epithelial cells in fetal intestine produce body improves histological scores, but in IBD may result from increased intest- chemerin to recruit macrophages. Am J not the clinical manifestations of DSS inal or colonic secretion. Furthermore, Physiol Gastrointest Liver Physiol 2009; colitis. Lin and colleagues9 speculate that pro-inflammatory cytokines induce adi- 297: G1–G10. 8 Elson CO, Sartor RB, Tennyson GS, Riddell this approach does not efficiently block pocytes to express chemerin but have RH. Experimental models of inflammatory 4,5 endogenous chemerin and suggest the no effect on hepatocytes (Figure 1). bowel disease. Gastroenterology 1995; use of chemerin knockout mice to per- Overall, the study by Lin and colleagues 109: 1344–1367. form confirmatory experiments. Despite demonstrates a role for chemerin in 9 Lin Y, Yang X, Yue W, Xu X, Li B, Zou L et al. this limitation, cultured colonic cells IBD pathophysiology in a commonly Chemerin aggravates DSS-induced colitis by 9 suppressing M2 macrophage polarization. from antibody-treated mice produce used rodent model. CMKLR1 is Cell Mol Immunol 2014; 4: 355–366. lower levels of TNF. Furthermore, induced in the colon tissue of DSS- 10 Bondue B, de Henau O, Luangsay S, colonic expression of arginase-1 is treated mice11 and serves as a receptor Devosse T, de Nadai P, Springael JY et al. induced. Again, the number of inflam- for chemerin and resolvin E1. Chemerin The Chemerin/ChemR23 system does not 9 affect the pro-inflammatory response of matory cells is not affected. Collectively, exacerbates and resolvin E1 prevents mouse and human macrophages ex vivo. 11 these data demonstrate that chemerin DSS colitis, and the underlying mecha- PLoS ONE 2012; 7: e40043. has a role in IBD pathology. nisms of the opposing effects of these 11 Ishida T, Yoshida M, Arita M, Nishitani Y, Elevated systemic chemerin is, how- ligands still need to be characterized. Nishiumi S, Masuda A et al. Resolvin E1, an endogenous lipid mediator derived from ever, not related to disease activity in Additional studies using different IBD eicosapentaenoic acid, prevents dextran 6 IBD patients. In colon biopsies of models, other strategies to block endo- sulfate sodium-induced colitis. Inflamm patients with ulcerative colitis, the genous chemerin action and experi- Bowel Dis 2010; 16: 87–95. expression of chemerin is higher in ments to reveal the role of chemerin in 12 Zabel BA, Ohyama T, Zuniga L, Kim JY, Johnston B, Allen SJ et al. Chemokine-like inflamed tissues and, importantly, is fur- human IBD are needed before chemerin receptor 1 expression by macrophages in ther increased in more severely inflamed targeting can be used as a novel approach vivo: regulation by TGF-beta and TLR tissues.9 Colon cells isolated from to treat IBD. ligands. Exp Hematol 2006; 34: 1106–1114.

Cellular & Molecular Immunology