CYSLTR2, encoding the G protein-coupled receptor cysteinyl-leukotriene receptor 2 (CysLTR2), is involved in multiple biological processes. Cysteinyl leukotrienes (CysLTs) can bind to CysLTR2, activating inflammatory responses. It is also part of signaling pathways related to G-protein-coupled receptor-mediated functions, and its genetic variations are associated with several diseases, highlighting its biological importance. Genetic models, such as gene knockout (KO) mouse models, can be valuable for studying its functions [2,3].

In atherosclerosis, CYSLTR2, along with P2RY6, was identified as a potential endogenous receptor of C16:0 ceramide-induced inflammasome activation in endothelial cells and macrophages. Inhibition of CYSLTR2, either genetically or pharmacologically, alleviated ceramide-induced atherosclerosis aggravation. CYSLTR2-deficient mice also showed mitigation of chronic-kidney-disease-aggravated atherosclerosis without affecting cholesterol or ceramide levels [1]. In the context of itch, Cysltr2 transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. Injection of leukotriene C4 (LTC4), which binds to CysLT2R, induced itch behaviors in wild-type mice but not in Cysltr2-deficient mice, suggesting its role in LTC4-driven acute and chronic itch.

In summary, CYSLTR2 plays a crucial role in inflammation-related biological processes. The use of KO mouse models has revealed its significance in diseases like atherosclerosis and itch. Understanding CYSLTR2's functions through these models provides insights into the mechanisms of these diseases, potentially paving the way for new therapeutic strategies targeting related signaling pathways.

References:

1. Zhang, Siting, Lin, Hui, Wang, Jiale, Sun, Jinpeng, Kong, Wei. 2025. Sensing ceramides by CYSLTR2 and P2RY6 to aggravate atherosclerosis. In Nature, 641, 476-485. doi:10.1038/s41586-025-08792-8. https://pubmed.ncbi.nlm.nih.gov/40049228/

2. Dos S Jesus, Talita, Dos S Costa, Ryan, Alcântara-Neves, Neuza Maria, Barreto, Maurício L, Figueiredo, Camila Alexandrina. 2019. Variants in the CYSLTR2 are associated with asthma, atopy markers and helminths infections in the Brazilian population. In Prostaglandins, leukotrienes, and essential fatty acids, 145, 15-22. doi:10.1016/j.plefa.2019.05.003. https://pubmed.ncbi.nlm.nih.gov/31126515/

3. Voisin, Tiphaine, Perner, Caroline, Messou, Marie-Angele, Austen, K Frank, Chiu, Isaac M. . The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch. In Proceedings of the National Academy of Sciences of the United States of America, 118, . doi:10.1073/pnas.2022087118. https://pubmed.ncbi.nlm.nih.gov/33753496/