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Neuropilin-1 high monocytes protect against neonatal inflammation

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, the underlying mechanisms of which remain poorly understood. In this study, we identified a subset of neonatal monocytes characterized with high levels of neuropilin-1 (Nrp1), termed Nrp1 high monocytes. Nrp1high monocytes displayed potent immunosuppressive activity as compared with their Nrp1low counterpart. Nrp1 deficiency in myeloid cells aggravated the severity of NEC, whereas adoptive transfer of Nrp1 highmonocytes led to remission of NEC. Mechanistic studies showed that Nrp1, via 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 observations uncover an important immunosuppressive axis in neonatal monocytes and provide a potential therapeutic strategy for inflammatory disorders in neonates.

ORGANISM(S): Mus musculus

PROVIDER: GSE263510 | GEO | 2024/04/12

REPOSITORIES: GEO

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Single-cell profiling of mouse spleen myeloid cells

Project description:Neonates are at higher risk of inflammatory disorders due to their immature immune system. The timely appearance of regulatory immune cells in early life contributes to the control of inflammation in neonates via induction of immunotolerance, the mechanisms underlying which remain poorly understood. In this study, we identified a subset of neonatal monocytes with high expression of transmembrane protein Neuropilin-1 (Nrp1), termed Nrp1high monocytes. Nrp1high monocytes displayed potent immunosuppressive activity and their frequencies declined in age-dependent manner. Deletion of Nrp1 in myeloid cells aggravated the severity of neonatal inflammatory disease necrotizing enterocolitis (NEC). Adoptive transfer of Nrp1high monocytes led to remission of NEC. Mechanistic studies showed that Nrp1, via binding with its ligand semaphorin-4a (Sema4a), induced intracellular p38-MAPK/mTOR signaling and activated transcription factor KLF4. KLF4 activation led to transcription of Nos2 and enhanced the production of nitric oxide, a key mediator of immunosuppression in monocytes. These observations uncover an important immunosuppressive axis in neonatal monocytes, and provides potential therapeutic strategy for inflammatory disorders in neonates.

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