Citation

Inflammation is characterized by the influx and activation of leukocytes to sites of tissue damage. Upon recruitment, immune cells become activated and can secrete proinflammatory cytokines and chemoattractants that can modulate cellular responses and leukocyte trafficking. However, if inflammation occurs inappropriately, it can lead to unwanted tissue damage to the host or can affect metabolic processes (e.g. glucose metabolism or bone metabolism). Evidence indicates inflammation also occurs in adipose tissue during obesity and that adipose tissue leukocytes secrete cytokines that can contribute to systemic, chronic inflammation. The mechanisms that regulate inflammation and mediate its effects on metabolism are not fully understood. To help clarify what factors mediate inflammation, we sought to determine the role that the chemerin receptor, CMKLR1, may play in mediating immune cell trafficking to inflamed tissue. We found CMKLR1 is expressed by murine peritoneal macrophages, which can migrate to chemerin in vitro. CMKLR1 was upregulated by TGF? and downregulated by pro-inflammatory cytokines and TLR ligands. Furthermore, we found that CMKLR1 exacerbated the progression of experimental murine autoimmune encephalomyelitis (EAE). Chemerin was expressed in inflamed central nervous system (CNS) tissue, and microglial cells and CNS-associated myeloid dendritic cells expressed CMKLR1 in mice with EAE. Additionally, we discovered CCRL2 as a novel receptor for chemerin and determined it is a non-signaling decoy receptor which may bind and present chemerin to CMKLR1. We found that CCRL2 is expressed by mouse mast cells and can enhance tissue swelling and tissue leukocyte infiltration during mast cell-dependent passive cutaneous anaphylaxis. In an attempt to uncover a role for chemerin/CMKLR1 in obesity development or obesity-related inflammation, we discovered an unexpected role for the pro-inflammatory cytokine, IL-17, in adipocyte metabolism. IL-17 was upregulated in obese adipose tissue by T cells. IL-17 KO mice were more susceptible to diet-induced obesity. IL-17 inhibited adipocyte development and insulin stimulated glucose uptake by adipocytes. Furthermore, young IL-17 deficient mice were more insulin sensitive than their WT counterparts. Overall, our data indicate a role for chemerin and chemerin receptors in leukocyte migration and function in inflammatory diseases, and suggest that IL-17 regulates metabolic responses associated with obesity.