Abstract
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 Nrp1high monocytes. Compared with their Nrp1low counterparts, Nrp1high monocytes displayed potent immunosuppressive activity. Nrp1 deficiency in myeloid cells aggravated the severity of NEC, whereas adoptive transfer of Nrp1high 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.
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Data availability
All data reported in this paper will be shared by the lead contact upon reasonable request. The current bulk RNA-seq, ATAC-seq and scRNA-seq data have been deposited in the NCBI Gene Expression Omnibus database and are publicly available as of the date of publication (GSE263510 for bulk RNA-seq and ATAC-seq data; GSE254449 for scRNA-seq data, respectively.).
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (No. 81925018 and 82130049 to J. Zhou; No. 82001660 to X. Zheng) and the China Postdoctoral Science Foundation (No. 2021M692406 to X. Zheng).
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JZ conceived and supervised this study. XZ performed most of the experiments, analyzed the data and wrote the manuscript. YZ participated in the animal model and flow cytometry analysis. WL, HJ and ZC performed the bulk RNA-seq, ATAC-seq and scRNA-seq analyses. FW and CJ provided the human peripheral blood samples. CH, RZ, YZ, HW, QL, ZYÂ and YY provided help in project design and manuscript revision. JZ wrote the manuscript with input from all of the authors.
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The authors declare no competing interests. J.Z. is an editorial board member of Cellular & Molecular Immunology, but she has not been involved in the peer review or the decision-making of the article.
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Zheng, X., Lei, W., Zhang, Y. et al. Neuropilin-1high monocytes protect against neonatal inflammation. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01157-7
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DOI: https://doi.org/10.1038/s41423-024-01157-7