Ccrl2, also known as Chemokine (C-C motif) receptor-like 2, is a seven-transmembrane domain receptor belonging to the chemokine receptor family. Unlike typical members, it does not promote chemotaxis and shares features with atypical chemokine receptors (ACKRs), yet it does not bind chemokines and lacks scavenging functions. Its only commonly recognized ligand is chemerin, a non-chemokine chemotactic protein. Ccrl2 is expressed by both leukocytes and non-hematopoietic cells, and it modulates leukocyte migration, which is crucial in various biological processes such as immune surveillance and inflammation [2].

In gene-knockout studies, CCRL2-/-ApoE-/-mice showed protection against plaque formation in the aortic arch's disturbed-flow areas, indicating that d-flow-induced CCRL2 promotes atherosclerotic plaque formation via a CCRL2-chemerin-β2 integrin axis [1]. In a Kras/p53Flox lung cancer cell 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 deletion of Ccrl2 gene in mice aggravated HFD-induced obesity and insulin resistance through increased adipose tissue macrophages infiltration [4,5]. Targeting CCRL2 with an antibody-drug conjugate in a tuberculosis mouse model enhanced the efficacy of the first-line TB treatment regimen [6].

In conclusion, Ccrl2 plays essential roles in multiple biological processes and disease conditions. Gene-knockout mouse models have been instrumental in revealing its functions in atherosclerosis, lung cancer, myelodysplastic syndrome, obesity-related insulin resistance, and tuberculosis treatment. These findings provide potential therapeutic targets for the prevention or treatment of these diseases.

References:

1. Tang, Chaojun, Chen, Guona, Wu, Fan, Zabel, Brian A, Zhu, Li. . Endothelial CCRL2 induced by disturbed flow promotes atherosclerosis via chemerin-dependent β2 integrin activation in monocytes. In Cardiovascular research, 119, 1811-1824. doi:10.1093/cvr/cvad085. https://pubmed.ncbi.nlm.nih.gov/37279540/

2. Schioppa, Tiziana, Sozio, Francesca, Barbazza, Ilaria, Sozzani, Silvano, Del Prete, Annalisa. 2020. Molecular Basis for CCRL2 Regulation of Leukocyte Migration. In Frontiers in cell and developmental biology, 8, 615031. doi:10.3389/fcell.2020.615031. https://pubmed.ncbi.nlm.nih.gov/33363177/

3. Sozio, Francesca, Schioppa, Tiziana, Laffranchi, Mattia, Del Prete, Annalisa, Sozzani, Silvano. . CCRL2 Expression by Specialized Lung Capillary Endothelial Cells Controls NK-cell Homing in Lung Cancer. In Cancer immunology research, 11, 1280-1295. doi:10.1158/2326-6066.CIR-22-0951. https://pubmed.ncbi.nlm.nih.gov/37343073/

4. Karantanos, Theodoros, Teodorescu, Patric, Arvanitis, Marios, Ghiaur, Gabriel, Jones, Richard J. 2023. CCRL2 affects the sensitivity of myelodysplastic syndrome and secondary acute myeloid leukemia cells to azacitidine. In Haematologica, 108, 1886-1899. doi:10.3324/haematol.2022.281444. https://pubmed.ncbi.nlm.nih.gov/36519323/

5. Xu, Min, Wang, Yu-Meng, Li, Wan-Qing, Tao, Lin-Fen, Li, Xi. 2020. Ccrl2 deficiency deteriorates obesity and insulin resistance through increasing adipose tissue macrophages infiltration. In Genes & diseases, 9, 429-442. doi:10.1016/j.gendis.2020.08.009. https://pubmed.ncbi.nlm.nih.gov/35224158/

6. Wang, Tianyin, Quijada, Darla, Ahmenda, Taha, Karantanos, Theodoros, Karanika, Styliani. 2024. Targeting CCRL2 enhances therapeutic outcomes in a tuberculosis mouse model. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.09.23.614576. https://pubmed.ncbi.nlm.nih.gov/39386470/