Il27ra, encoding the interleukin-27 receptor alpha subunit, is a cytokine receptor. IL-27/Il27ra signaling is involved in multiple biological processes, including immunomodulation, metabolism, and cell differentiation. It activates signaling pathways such as p38 MAPK-PGC-1α, STAT1, and STAT3, influencing various physiological functions [1,4,5].

Gene knockout models have provided key insights. In Il27ra-deleted mice, HSC functional decline and myeloid bias are rescued, suggesting that age-induced Il27ra signaling impairs hematopoietic stem cells [2]. In Il27ra-deficient pregnant mice, transfer of Ptgs2+/COX-2+ macrophages prevents fetal loss, as IL-27 secreted by endometrial stromal cells via FBP-mediated pathways promotes decidual COX-2+ M2-like macrophage differentiation [3]. C57BL/6 mice lacking Il27ra develop POI symptoms when on a high-fat diet, including lipid deposition, ovarian macrophage aging, and reduced follicle count, indicating that impaired IL-27 signaling sensitizes POI induction [6]. Also, Il27ra-deficient γδ T cells are more pathogenic in an imiquimod-induced murine psoriasis model, highlighting IL-27/Il27ra signaling's role in restraining γδ T17-mediated inflammation [7].

In conclusion, Il27ra is crucial in immunological and metabolic regulation. Studies using Il27ra knockout mouse models have revealed its significance in diseases like hematopoietic disorders, pregnancy-related conditions, premature ovarian insufficiency, and psoriasis. Understanding Il27ra's functions provides potential therapeutic targets for these disease areas.

References:

1. Wang, Qian, Li, Dehai, Cao, Guangchao, Flavell, Richard A, Yin, Zhinan. 2021. IL-27 signalling promotes adipocyte thermogenesis and energy expenditure. In Nature, 600, 314-318. doi:10.1038/s41586-021-04127-5. https://pubmed.ncbi.nlm.nih.gov/34819664/

2. He, Hanqing, Xu, Panglian, Zhang, Xiaofei, Ju, Zhenyu, Wang, Jianwei. . Aging-induced IL27Ra signaling impairs hematopoietic stem cells. In Blood, 136, 183-198. doi:10.1182/blood.2019003910. https://pubmed.ncbi.nlm.nih.gov/32305041/

3. Zhou, Wen-Jie, Yang, Hui-Li, Mei, Jie, Jin, Li-Ping, Li, Ming-Qing. 2022. Fructose-1,6-bisphosphate prevents pregnancy loss by inducing decidual COX-2+ macrophage differentiation. In Science advances, 8, eabj2488. doi:10.1126/sciadv.abj2488. https://pubmed.ncbi.nlm.nih.gov/35196096/

4. Brownlie, Rebecca J, Kennedy, Ruth, Wilson, Erica B, Westhead, David R, Klein, Ulf. . Cytokine receptor IL27RA is an NF-κB-responsive gene involved in CD38 upregulation in multiple myeloma. In Blood advances, 7, 3874-3890. doi:10.1182/bloodadvances.2022009044. https://pubmed.ncbi.nlm.nih.gov/36867577/

5. Martin, Emmanuel, Winter, Sarah, Garcin, Cécile, Fischer, Alain, Latour, Sylvain. 2024. Role of IL-27 in Epstein-Barr virus infection revealed by IL-27RA deficiency. In Nature, 628, 620-629. doi:10.1038/s41586-024-07213-6. https://pubmed.ncbi.nlm.nih.gov/38509369/

6. Zhang, Xin-Yan, Wang, Cheng-Jie, Shen, Hui-Hui, Wang, Wen-Jun, Li, Ming-Qing. 2024. Impaired IL-27 signaling aggravates macrophage senescence and sensitizes premature ovarian insufficiency induction by high-fat diet. In Biochimica et biophysica acta. Molecular basis of disease, 1870, 167469. doi:10.1016/j.bbadis.2024.167469. https://pubmed.ncbi.nlm.nih.gov/39153664/

7. Zhang, Mingyue, Li, Dehai, Zhu, Jing, Yin, Zhinan, Wang, Qian. 2024. IL-27 disturbs lipid metabolism and restrains mitochondrial activity to inhibit γδ T17 cell-mediated skin inflammation. In Cell death & disease, 15, 491. doi:10.1038/s41419-024-06887-0. https://pubmed.ncbi.nlm.nih.gov/38982043/