Substance P promotes epidural fibrosis via induction of type 2 macrophages  

作　　者：Feng Hua Hao-Ran Wang Yun-Feng Bai Jin-Peng Sun Wei-Shun Wang Ying Xu Ming-Shun Zhang Jun Liu 

机构地区：[1]Department of Orthopedics,The Second Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu Province,China [2]Department of Orthopedics,Sir Run Run Hospital,Nanjing Medical University,Nanjing,Jiangsu Province,China [3]Department of Intensive Care Unit,Nanjing Drum Tower Hospital,the Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu Province,China [4]NHC Key Laboratory of Antibody Technique,Jiangsu Province Engineering Research Center of Antibody Drug,Department of Immunology,Nanjing Medical University,Nanjing,Jiangsu Province,China

出　　处：《Neural Regeneration Research》2023年第10期2252-2259,共8页中国神经再生研究（英文版）

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);"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)。

摘　　要：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.

关 键 词：dorsal root ganglion epidural fibrosis LAMINECTOMY MACROPHAGE MITOCHONDRIA neurokinin receptor 1 neutrophil extracellular traps sphingomyelin synthase 2 substance P 

分 类 号：R651.2[医药卫生—外科学]