{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CMKLR1, also known as ChemR23, is a versatile G protein–coupled receptor that mediates the actions of its ligands—most notably chemerin and resolvin E1—to integrate immune, metabolic, vascular, and tissue‐remodeling signals. In the immune system, CMKLR1 is expressed on dendritic cells, macrophages, monocytes, and natural killer cells, where its activation by protease‐processed chemerin initiates calcium mobilization, chemotaxis, and even integrin‐dependent adhesion that collectively contribute to both proinflammatory cell recruitment and the resolution of inflammation through enhanced phagocytosis and macrophage repolarization."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " In adipose tissue, CMKLR1 is found in both adipocytes and stromal–vascular cells and plays a pivotal role in regulating adipogenesis and lipid as well as glucose homeostasis; alterations in CMKLR1 signaling are linked to obesity, insulin resistance, and related metabolic disturbances."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "10"}]}, {"type": "t", "text": " In the vasculature, endothelial and smooth muscle cell expression of CMKLR1 mediates chemerin‐induced angiogenesis and vasoconstriction, thereby linking local adipose–tissue signals to the control of arterial tone and blood pressure."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In joint and skin tissues, CMKLR1 activation on chondrocytes and synovial cells promotes the production of proinflammatory cytokines and matrix metalloproteases, contributing to the initiation and propagation of inflammatory disorders, such as psoriasis and rheumatoid arthritis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "16"}]}, {"type": "t", "text": " Moreover, CMKLR1 is functionally relevant in reproductive and endocrine tissues; its expression in ovarian granulosa cells modulates steroidogenesis and, in pancreatic β‐cells, it supports proper glucose‐stimulated insulin secretion, thereby linking inflammatory signals to reproductive function and systemic glucose homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "19"}]}, {"type": "t", "text": " Finally, genetic variations in the CMKLR1 gene have been associated with adverse outcomes in non–small cell lung cancer, highlighting its broader pathophysiological impact."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " Collectively, these findings establish CMKLR1 as a central integrator that links adipose‐derived signals and protease–mediated ligand activation to key processes in immune cell trafficking, energy metabolism, vascular regulation, and tissue remodeling.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Brian A Zabel, Samantha J Allen, Paulina Kulig, et al. 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