Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Immunology, Tianjin Medical University, Tianjin, 300070, China.
Institute of Pediatric Health and Disease, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
Cell Mol Immunol. 2024 Jun;21(6):575-588. doi: 10.1038/s41423-024-01157-7. Epub 2024 Apr 17.
Neonates are susceptible to inflammatory disorders such as necrotizing enterocolitis (NEC) due to their immature immune system. The timely appearance of regulatory immune cells in early life contributes to the control of inflammation in neonates, yet the underlying mechanisms of which remain poorly understood. In this study, we identified a subset of neonatal monocytes characterized by high levels of neuropilin-1 (Nrp1), termed Nrp1 monocytes. Compared with their Nrp1 counterparts, Nrp1 monocytes displayed potent immunosuppressive activity. Nrp1 deficiency in myeloid cells aggravated the severity of NEC, whereas adoptive transfer of Nrp1 monocytes led to remission of NEC. Mechanistic studies showed that Nrp1, by binding to its ligand Sema4a, induced intracellular p38-MAPK/mTOR signaling and activated the transcription factor KLF4. KLF4 transactivated Nos2 and enhanced the production of nitric oxide (NO), a key mediator of immunosuppression in monocytes. These findings reveal an important immunosuppressive axis in neonatal monocytes and provide a potential therapeutic strategy for treating inflammatory disorders in neonates.
新生儿由于其免疫系统不成熟，易发生炎症性疾病，如坏死性小肠结肠炎（NEC）。调节性免疫细胞在生命早期的及时出现有助于控制新生儿的炎症，但其中的潜在机制仍知之甚少。在这项研究中，我们鉴定出一群高水平表达神经纤毛蛋白-1（Nrp1）的新生儿单核细胞，称为 Nrp1 单核细胞。与 Nrp1 单核细胞相比，Nrp1 单核细胞表现出强大的免疫抑制活性。髓系细胞中 Nrp1 的缺失加重了 NEC 的严重程度，而 Nrp1 单核细胞的过继转移则导致 NEC 的缓解。机制研究表明，Nrp1 通过与其配体 Sema4a 结合，诱导细胞内 p38-MAPK/mTOR 信号，并激活转录因子 KLF4。KLF4 反式激活 Nos2 并增强一氧化氮（NO）的产生，NO 是单核细胞中免疫抑制的关键介质。这些发现揭示了新生儿单核细胞中一个重要的免疫抑制轴，并为治疗新生儿炎症性疾病提供了一种潜在的治疗策略。
