Gpr37, a G protein-coupled receptor, is highly expressed in the central nervous system, especially in the spinal cord and oligodendrocytes. It has been implicated in multiple signaling pathways and is of great biological importance in various physiological and pathological processes [4,5]. Its ligands include neuroprotectin D1 (NPD1) and prosaptide TX14, which can trigger calcium-related signaling [1]. Genetic mouse models have been crucial for studying Gpr37 functions.

In Gpr37-deficient mice, deficits in macrophage phagocytic activity are observed, leading to delayed resolution of inflammatory pain [1]. Macrophages lacking Gpr37 also show dysregulations of pro-and anti-inflammatory cytokines, shifting from M2-to M1-like phenotypes [3]. In models of colorectal cancer liver metastases, Gpr37 depletion suppresses liver metastasis, reduces CRC cell glycolysis, and abrogates neutrophil recruitment in the tumor microenvironment [2]. Also, Gpr37-deficient CRC cells are more susceptible to ferroptosis as Gpr37 protects cancer cells from it by upregulating SCD1 expression via the MAPK-p38 signaling pathway [6]. Moreover, mice lacking Gpr37 exhibit increased death and hypothermia following infection challenges, indicating Gpr37's protective role in sepsis [7].

In conclusion, Gpr37 plays essential roles in macrophage-mediated processes such as phagocytosis, inflammatory pain resolution, and protection against infection-induced sepsis. In cancer, it promotes colorectal cancer progression through various mechanisms. The study of Gpr37 using gene-knockout mouse models has significantly advanced our understanding of its functions in these disease areas, potentially paving the way for new therapeutic strategies.

References:

1. Bang, Sangsu, Xie, Ya-Kai, Zhang, Zhi-Jun, Xu, Zhen-Zhong, Ji, Ru-Rong. 2018. GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain. In The Journal of clinical investigation, 128, 3568-3582. doi:10.1172/JCI99888. https://pubmed.ncbi.nlm.nih.gov/30010619/

2. Zhou, Jiamin, Xu, Weiqi, Wu, Yibin, Wang, Lu, Mao, Anrong. 2023. GPR37 promotes colorectal cancer liver metastases by enhancing the glycolysis and histone lactylation via Hippo pathway. In Oncogene, 42, 3319-3330. doi:10.1038/s41388-023-02841-0. https://pubmed.ncbi.nlm.nih.gov/37749229/

3. Zhang, Qin, Bang, Sangsu, Chandra, Sharat, Ji, Ru-Rong. 2022. Inflammation and Infection in Pain and the Role of GPR37. In International journal of molecular sciences, 23, . doi:10.3390/ijms232214426. https://pubmed.ncbi.nlm.nih.gov/36430912/

4. Marazziti, Daniela. 2023. GPR37 and Related Receptors: Disease Regulation. In International journal of molecular sciences, 24, . doi:10.3390/ijms24076722. https://pubmed.ncbi.nlm.nih.gov/37047695/

5. Bolinger, Andrew A, Frazier, Andrew, La, Jun-Ho, Allen, John A, Zhou, Jia. 2023. Orphan G Protein-Coupled Receptor GPR37 as an Emerging Therapeutic Target. In ACS chemical neuroscience, 14, 3318-3334. doi:10.1021/acschemneuro.3c00479. https://pubmed.ncbi.nlm.nih.gov/37676000/

6. Zhou, Jiamin, He, Xigan, Dai, Weixing, Wang, Lu, Mao, Anrong. 2024. GPR37 promotes colorectal cancer against ferroptosis by reprogramming lipid metabolism via p38-SCD1 axis. In Apoptosis : an international journal on programmed cell death, 29, 1988-2001. doi:10.1007/s10495-024-02018-4. https://pubmed.ncbi.nlm.nih.gov/39306652/

7. Bang, Sangsu, Donnelly, Christopher R, Luo, Xin, Derbyshire, Emily R, Ji, Ru-Rong. 2021. Activation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice. In Nature communications, 12, 1704. doi:10.1038/s41467-021-21940-8. https://pubmed.ncbi.nlm.nih.gov/33731716/