In response to spinal surgery,neurons secrete a large amount of substance P into the epidural area.Substance P is involved in macrophage differentiation and fibrotic disease.However,the specific roles and mechanisms o...In response to spinal surgery,neurons secrete a large amount of substance P into the epidural area.Substance P is involved in macrophage differentiation and fibrotic disease.However,the specific roles and mechanisms of substance P in epidural fibrosis remain unclear.In this study,we established a mouse model of L1–L3 laminectomy and found that dorsal root ganglion neurons and the macrophages infiltrating into the wound area released sphingolipids.In vitro experiments revealed that type 1 macrophages secreted substance P,which promoted differentiation of type 1 macrophages towards a type 2 phenotype.High-throughput mRNA-seq analysis revealed that the sphingolipid metabolic pathway may be involved in the regulation of type 2 macrophages by substance P.Specifically,sphingomyelin synthase 2,a component of the sphingolipid metabolic pathway,promoted M2 differentiation in substance P-treated macrophages,while treating the macrophages with LY93,a sphingomyelin synthase 2 inhibitor,suppressed M2 differentiation.In addition,substance P promoted the formation of neutrophil extracellular traps,which further boosted M2 differentiation.Blocking substance P with the neurokinin receptor 1 inhibitor RP67580 decreased the number of M2 macrophages in the wound area after spinal surgery and alleviated epidural fibrosis,as evidenced by decreased fibronectin,α-smooth muscle actin,and collagen I in the scar tissue.These results demonstrated that substance P promotes M2 macrophage differentiation in epidural fibrosis via sphingomyelin synthase 2 and neutrophil extracellular traps.These findings provide a novel strategy for the treatment of epidural fibrosis.展开更多
Parasitic helminths,taxonomically comprising trematodes,cestodes,and nematodes,are multicellular invertebrates widely disseminated in nature and have afflicted humans continuously for a long time.Helminths play potent...Parasitic helminths,taxonomically comprising trematodes,cestodes,and nematodes,are multicellular invertebrates widely disseminated in nature and have afflicted humans continuously for a long time.Helminths play potent roles in the host by generating a variety of novel molecules,including some excretory/secretory products and others that are involved in intracellular material exchange and information transfer as well as the initiation or stimulation of immune and metabolic activation.The helminth-derived molecules have developed powerful and diverse immunosuppressive effects to achieve immune evasion for parasite survival and establish chronic infections.However,they also improve autoimmune and allergic inflammatory responses and promote metabolic homeostasis by promoting metabolic reprogramming of various immune functions,and then inducing alternatively activated macrophages,T helper 2 cells,and regulatory T cell-mediated immune responses.Therefore,a deeper exploration of the immunopathogenic mechanism and immune regulatory mechanisms of helminth-derived molecules exerted in the host is crucial for understanding host-helminth interactions,as well as the development of therapeutic drugs for infectious or non-infectious diseases.In this review,we focus on the properties of helminth-derived molecules to give an overview of the most recent scientific knowledge about their pathogenic and pharmacopeial roles in immune-metabolic homeostasis.展开更多
Regulatory T cells(Tregs)are fundamentally important for maintaining systemic immune homeostasis and are also required for immune tolerance at the maternal-fetal interface during pregnancy.Recent studies have suggeste...Regulatory T cells(Tregs)are fundamentally important for maintaining systemic immune homeostasis and are also required for immune tolerance at the maternal-fetal interface during pregnancy.Recent studies have suggested that epigenetic regulation is critically involved in Treg development and function.However,the role of H3K36me has not yet been investigated.Here,we found that the H3K36me2 methyltransferase Nsd2 was highly expressed in Tregs.Although loss of Nsd2 did not impair systemic Treg development or function,the level of Tregs at the maternal-fetal interface was significantly decreased in pregnant Nsd2 conditional knockout mice.Consequently,maternal-fetal immune tolerance was disrupted in the absence of Nsd2 in Tregs,and the pregnant mice showed severe fetal loss.Mechanistically,Nsd2 was found to upregulate CXCR4 expression via H3K36me2 modification to promote Treg cell recruitment into the decidua and suppress the anti-fetal immune response.Overall,our data identified Nsd2 as a critical epigenetic regulator of Treg recruitment for maternal-fetal tolerance.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82172486(to JL),82171738(to MSZ),81671563(to MSZ)Jiangsu Provincial Commission of Health and Family Planning,No.JSWST-028(to JL)+1 种基金"Six One"Project of Jiangsu Province,No.LGY2016018(to JL)Jiangsu Provincial Personnel Department"the Great of Six Talented Man Peak"Project,No.WSW-040(to JL)。
文摘In response to spinal surgery,neurons secrete a large amount of substance P into the epidural area.Substance P is involved in macrophage differentiation and fibrotic disease.However,the specific roles and mechanisms of substance P in epidural fibrosis remain unclear.In this study,we established a mouse model of L1–L3 laminectomy and found that dorsal root ganglion neurons and the macrophages infiltrating into the wound area released sphingolipids.In vitro experiments revealed that type 1 macrophages secreted substance P,which promoted differentiation of type 1 macrophages towards a type 2 phenotype.High-throughput mRNA-seq analysis revealed that the sphingolipid metabolic pathway may be involved in the regulation of type 2 macrophages by substance P.Specifically,sphingomyelin synthase 2,a component of the sphingolipid metabolic pathway,promoted M2 differentiation in substance P-treated macrophages,while treating the macrophages with LY93,a sphingomyelin synthase 2 inhibitor,suppressed M2 differentiation.In addition,substance P promoted the formation of neutrophil extracellular traps,which further boosted M2 differentiation.Blocking substance P with the neurokinin receptor 1 inhibitor RP67580 decreased the number of M2 macrophages in the wound area after spinal surgery and alleviated epidural fibrosis,as evidenced by decreased fibronectin,α-smooth muscle actin,and collagen I in the scar tissue.These results demonstrated that substance P promotes M2 macrophage differentiation in epidural fibrosis via sphingomyelin synthase 2 and neutrophil extracellular traps.These findings provide a novel strategy for the treatment of epidural fibrosis.
基金supported by the National Natural Science Foundation of China(Z.P.X,Grant No.82472311)the Natural Science Foundation of Jiangsu Province(Z.P.X,Grant No.BK20211586)+3 种基金the Funding of the State Key Laboratory of Reproductive Medicine(Z.P.X,Grant Nos.SKLRM-2021C3 and SKLRM-2024B14)the Medical Scientific Research Project of Jiangsu Provincial Health Commission(Z.P.X,Grant No.Z2021004)the National Sharing Service Platform for Parasite Resources(Z.P.X,Grant No.TDRC-2019-194-30)the Qing Lan Project of Jiangsu Province of China(Z.P.X,Grant No.KY101R202127).
文摘Parasitic helminths,taxonomically comprising trematodes,cestodes,and nematodes,are multicellular invertebrates widely disseminated in nature and have afflicted humans continuously for a long time.Helminths play potent roles in the host by generating a variety of novel molecules,including some excretory/secretory products and others that are involved in intracellular material exchange and information transfer as well as the initiation or stimulation of immune and metabolic activation.The helminth-derived molecules have developed powerful and diverse immunosuppressive effects to achieve immune evasion for parasite survival and establish chronic infections.However,they also improve autoimmune and allergic inflammatory responses and promote metabolic homeostasis by promoting metabolic reprogramming of various immune functions,and then inducing alternatively activated macrophages,T helper 2 cells,and regulatory T cell-mediated immune responses.Therefore,a deeper exploration of the immunopathogenic mechanism and immune regulatory mechanisms of helminth-derived molecules exerted in the host is crucial for understanding host-helminth interactions,as well as the development of therapeutic drugs for infectious or non-infectious diseases.In this review,we focus on the properties of helminth-derived molecules to give an overview of the most recent scientific knowledge about their pathogenic and pharmacopeial roles in immune-metabolic homeostasis.
基金supported by the National Key R&D Program of China (2018YFC1003900)the National Natural Science Foundation of China (Grant Number 82001653 to LZ and 31970828 to XW)Jiangsu Outstanding Young Investigator Program (BK20200030).
文摘Regulatory T cells(Tregs)are fundamentally important for maintaining systemic immune homeostasis and are also required for immune tolerance at the maternal-fetal interface during pregnancy.Recent studies have suggested that epigenetic regulation is critically involved in Treg development and function.However,the role of H3K36me has not yet been investigated.Here,we found that the H3K36me2 methyltransferase Nsd2 was highly expressed in Tregs.Although loss of Nsd2 did not impair systemic Treg development or function,the level of Tregs at the maternal-fetal interface was significantly decreased in pregnant Nsd2 conditional knockout mice.Consequently,maternal-fetal immune tolerance was disrupted in the absence of Nsd2 in Tregs,and the pregnant mice showed severe fetal loss.Mechanistically,Nsd2 was found to upregulate CXCR4 expression via H3K36me2 modification to promote Treg cell recruitment into the decidua and suppress the anti-fetal immune response.Overall,our data identified Nsd2 as a critical epigenetic regulator of Treg recruitment for maternal-fetal tolerance.
