Ccrl2, a seven-transmembrane domain receptor, belongs to the chemokine receptor family. Unlike typical members, it doesn't promote chemotaxis and shares features with atypical chemokine receptors. Its only commonly recognized ligand is chemerin. Ccrl2 is expressed by both leukocytes and non-hematopoietic cells and is involved in regulating leukocyte migration and immune responses [2].

In gene-knockout models, Ccrl2 -/- ApoE -/- mice showed protection against plaque formation in the aortic arch's disturbed-flow areas, indicating that disturbed-flow-induced Ccrl2 promotes atherosclerotic plaque formation via a Ccrl2-chemerin-β2 integrin axis [1]. In a Kras/p53Flox lung cancer model, Ccrl2 constitutive or conditional endothelial cell targeted ablation promoted tumor progression due to reduced recruitment of mature NK cells, suggesting Ccrl2 controls NK-cell homing in lung cancer [3]. Ccrl2 knockdown in MDS/sAML cell lines increased their sensitivity to azacitidine, and Ccrl2 deletion enhanced azacitidine's efficacy in an MDS-L xenograft model, showing its role in modulating the sensitivity of these cells to azacitidine [4]. Ccrl2 -/- mice had accelerated melanoma growth, impaired antitumor immunity, and reduced immunostimulatory macrophages and T-cell responses, revealing its role in activating immunostimulatory macrophages and potentiating antitumor T-cell response [5]. Ccrl2 -/- mice also had a lower density of vessels in the developing retina, reduced pathological angiogenesis, and increased vessel pruning and endothelial cell apoptosis, indicating Ccrl2 regulates angiogenesis [6]. Systemic deletion of Ccrl2 gene aggravated HFD-induced obesity and insulin resistance, with increased VAT inflammation and M1/M2 macrophages ratio due to enhanced macrophages chemotaxis [7].

In conclusion, Ccrl2 plays crucial roles in various biological processes and disease conditions. Gene-knockout mouse models have revealed its functions in atherosclerosis, lung cancer, MDS/sAML, melanoma, angiogenesis, obesity, and insulin resistance. These findings highlight Ccrl2 as a potential therapeutic target for these diseases.