Cmklr1, also known as ChemR23 or chemerin receptor 1, is a chemoattractant G protein-coupled receptor that responds to the adipokine chemerin. It is highly expressed in innate immune cells like macrophages and neutrophils. The signaling pathways of Cmklr1 can lead to both pro-and anti-inflammatory effects, depending on ligands and physiological contexts. It is involved in multiple biological processes such as lipid metabolism, immune regulation, and thermogenesis [4,8].

In mice, deficiency of intestinal epithelial cell-specific Cmklr1 confers high susceptibility to microbiota-driven neutrophilic colon inflammation and subsequent tumorigenesis due to reduced lactoperoxidase expression, which leads to outgrowth of gram-negative bacteria [1]. In allogeneic bone marrow transplantation, WT mice transplanted with an allogeneic graft from Cmklr1-KO donors had worse survival and more severe gastrointestinal graft-versus-host disease (GvHD), characterized by massive neutrophil infiltration and tissue damage [2]. Genetic and pharmacologic suppression of Cmklr1 in clear cell renal cell carcinoma (ccRCC) models suppressed lipid formation and induced cell death, impeding ccRCC growth [3]. Lack of the chemerin/Cmklr1 axis in a mouse model of cutaneous Staphylococcus aureus infection increased neutrophil-mediated host defense, while chemerin overexpression exacerbated the infection [5]. CMKLR1-KO female mice showed attenuated androgen-induced lipid accumulation in adipose tissues [6]. Adipocytic Cmklr1 deficiency enhanced cold-induced thermogenic beige fat via potentiating type 2 innate immune responses and protected against diet-induced obesity [7].

In conclusion, Cmklr1 is crucial in immune regulation, lipid metabolism, and thermogenesis. Gene knockout mouse models have revealed its significant roles in diseases such as colitis, GvHD, ccRCC, cutaneous infections, and obesity-related metabolic disorders. These findings provide insights into potential therapeutic strategies targeting Cmklr1 for these diseases.

References:

1. Lin, Yuli, Cai, Qian, Luo, Yaxin, Yang, Huifan, He, Rui. 2022. Epithelial chemerin-CMKLR1 signaling restricts microbiota-driven colonic neutrophilia and tumorigenesis by up-regulating lactoperoxidase. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2205574119. doi:10.1073/pnas.2205574119. https://pubmed.ncbi.nlm.nih.gov/35858331/

2. Dander, Erica, Vinci, Paola, Vetrano, Stefania, Sozzani, Silvano, D'Amico, Giovanna. 2023. The chemerin/CMKLR1 axis regulates intestinal graft-versus-host disease. In JCI insight, 8, . doi:10.1172/jci.insight.154440. https://pubmed.ncbi.nlm.nih.gov/36883565/

3. Wang, Dazhi, Mahmud, Iqbal, Thakur, Vijay S, Brugarolas, James, Welford, Scott M. . GPR1 and CMKLR1 Control Lipid Metabolism to Support the Development of Clear Cell Renal Cell Carcinoma. In Cancer research, 84, 2141-2154. doi:10.1158/0008-5472.CAN-23-2926. https://pubmed.ncbi.nlm.nih.gov/38640229/

4. Zhang, Xuan, Weiß, Tina, Cheng, Mary Hongying, Beck-Sickinger, Annette G, Zhang, Cheng. 2023. Structural basis of CMKLR1 signaling induced by chemerin9. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.06.09.544295. https://pubmed.ncbi.nlm.nih.gov/37333145/

5. Chen, Yu, Song, Yan, Wang, Zhe, Li, Huabin, He, Rui. 2024. The chemerin-CMKLR1 axis in keratinocytes impairs innate host defense against cutaneous Staphylococcus aureus infection. In Cellular & molecular immunology, 21, 533-545. doi:10.1038/s41423-024-01152-y. https://pubmed.ncbi.nlm.nih.gov/38532043/

6. Huang, Binbin, Zhao, Huashan, Huang, Chen, Niu, Jianmin, Zhang, Jian V. 2020. CMKLR1 deficiency attenuates androgen-induced lipid accumulation in mice. In American journal of physiology. Endocrinology and metabolism, 318, E371-E380. doi:10.1152/ajpendo.00176.2019. https://pubmed.ncbi.nlm.nih.gov/31910029/

7. Lin, Yuli, Xiao, Liuling, Cai, Qian, Li, Xi, He, Rui. . The chemerin-CMKLR1 axis limits thermogenesis by controlling a beige adipocyte/IL-33/type 2 innate immunity circuit. In Science immunology, 6, . doi:10.1126/sciimmunol.abg9698. https://pubmed.ncbi.nlm.nih.gov/34330814/

8. Zhang, Xuan, Weiß, Tina, Cheng, Mary Hongying, Beck-Sickinger, Annette G, Zhang, Cheng. 2023. Structural basis of G protein-Coupled receptor CMKLR1 activation and signaling induced by a chemerin-derived agonist. In PLoS biology, 21, e3002188. doi:10.1371/journal.pbio.3002188. https://pubmed.ncbi.nlm.nih.gov/38055679/