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...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^(high) monocytes.Compared with their Nrp1low counterparts,Nrp1^(high) monocytes displayed potent immunosuppressive activity.Nrp1 deficiency in myeloid cells aggravated the severity of NEC,whereas adoptive transfer of Nrp1^(high) 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.展开更多
基金National Natural Science Foundation of China(No.81925018 and 82130049 to J.ZhouNo.82001660 to X.Zheng)China Postdoctoral Science Foundation(No.2021M692406 to X.Zheng).
文摘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^(high) monocytes.Compared with their Nrp1low counterparts,Nrp1^(high) monocytes displayed potent immunosuppressive activity.Nrp1 deficiency in myeloid cells aggravated the severity of NEC,whereas adoptive transfer of Nrp1^(high) 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.
