Gpr174, a G-protein-coupled receptor, is widely expressed in immune cells like B and T lymphocytes, dendritic cells, and regulatory T cells (Tregs) [2,3,5,6]. It is involved in multiple biological processes, such as immunity regulation and neovascularization, and is associated with the Gαs/cAMP/PKA signal pathway [1]. Lysophosphatidylserine (lysoPS) has been identified as its endogenous ligand [4,7,8].

In gene knockout studies, Gpr174-deficient Tregs in mice potentiated blood flow recovery after hindlimb ischemia by upregulating AREG expression, suggesting Gpr174 negatively regulates angiogenesis in ischemic injury [1]. Gpr174 knockout in mice alleviated DSS-induced colitis by regulating dendritic cell maturation, with Gpr174 involved in TNF-α (NF-κB) signaling, leukocyte transendothelial migration, and Th1/Th2 cell differentiation pathways [2]. Deleting Gpr174 from male B cells in mice led to more efficient follicular centre positioning, more germinal centres, and increased susceptibility to B-cell-dependent experimental autoimmune encephalomyelitis, revealing its role in sexual dimorphism of humoral immunity [3]. Gpr174-deficient mice were resistant to LPS and CLP-induced inflammatory shock, as Gpr174-deficient Treg cells promoted M2 macrophage polarization and decreased pro-inflammatory cytokine secretions in sepsis [6]. Also, Gpr174 knockout in Ang II-treated mice attenuated retinopathy by reducing inflammation via the PI3K/AKT signaling pathway [9].

In conclusion, Gpr174 plays a crucial role in immune regulation, angiogenesis, and disease development. Gene knockout mouse models have revealed its negative regulation in angiogenesis during ischemic injury, its role in maintaining immune homeostasis in colitis, its contribution to sexual dimorphism in humoral immunity, its influence on macrophage polarization and cytokine secretion in sepsis, and its pro-inflammatory role in hypertensive retinopathy. These findings suggest Gpr174 could be a potential target for treating ischemic vascular diseases, IBD, autoimmune diseases, sepsis, and hypertensive retinopathy.

References:

1. Liu, Jin, Pan, Lihong, Hong, Wenxuan, Ge, Junbo, Sun, Aijun. 2022. GPR174 knockdown enhances blood flow recovery in hindlimb ischemia mice model by upregulating AREG expression. In Nature communications, 13, 7519. doi:10.1038/s41467-022-35159-8. https://pubmed.ncbi.nlm.nih.gov/36473866/

2. Wei, Wei, Mu, Sucheng, Han, Yi, Yang, Yilin, Song, Zhenju. 2022. Gpr174 Knockout Alleviates DSS-Induced Colitis via Regulating the Immune Function of Dendritic Cells. In Frontiers in immunology, 13, 841254. doi:10.3389/fimmu.2022.841254. https://pubmed.ncbi.nlm.nih.gov/35669778/

3. Zhao, Ruozhu, Chen, Xin, Ma, Weiwei, Wang, Jianbin, Qi, Hai. 2019. A GPR174-CCL21 module imparts sexual dimorphism to humoral immunity. In Nature, 577, 416-420. doi:10.1038/s41586-019-1873-0. https://pubmed.ncbi.nlm.nih.gov/31875850/

4. Nie, Yingying, Qiu, Zeming, Chen, Sijia, Cyster, Jason G, Zheng, Sanduo. 2023. Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling. In Nature communications, 14, 5901. doi:10.1038/s41467-023-41654-3. https://pubmed.ncbi.nlm.nih.gov/37737235/

5. Wolf, Elise W, Howard, Zachary P, Duan, Lihui, Xu, Ying, Cyster, Jason G. 2022. GPR174 signals via Gαs to control a CD86-containing gene expression program in B cells. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2201794119. doi:10.1073/pnas.2201794119. https://pubmed.ncbi.nlm.nih.gov/35639700/

6. Qiu, Dongze, Chu, Xun, Hua, Laiqing, Tong, Chaoyang, Song, Zhenju. 2019. Gpr174-deficient regulatory T cells decrease cytokine storm in septic mice. In Cell death & disease, 10, 233. doi:10.1038/s41419-019-1462-z. https://pubmed.ncbi.nlm.nih.gov/30850582/

7. Liu, Guibing, Li, Xiu, Wang, Yujing, Zhang, Xuan, Gong, Weimin. 2023. Structural basis for ligand recognition and signaling of the lysophosphatidylserine receptors GPR34 and GPR174. In PLoS biology, 21, e3002387. doi:10.1371/journal.pbio.3002387. https://pubmed.ncbi.nlm.nih.gov/38048360/

8. Liang, Jiale, Inoue, Asuka, Ikuta, Tatsuya, Huang, Zhiwei, He, Yuanzheng. 2023. Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation. In Nature communications, 14, 1012. doi:10.1038/s41467-023-36575-0. https://pubmed.ncbi.nlm.nih.gov/36823105/

9. Yue, Jianzhong, Zhao, Xin. 2019. GPR174 suppression attenuates retinopathy in angiotensin II (Ang II)-treated mice by reducing inflammation via PI3K/AKT signaling. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 122, 109701. doi:10.1016/j.biopha.2019.109701. https://pubmed.ncbi.nlm.nih.gov/31918274/