Spinal astrocyte-derived interleukin-17A promotes pain hypersensitivity in bone cancer mice  

作　　者：Huizhu Liu Xuejing Lv Xin Zhao Lanxing Yi Ning Lv Wendong Xu Yuqiu Zhang 

机构地区：[1]Department of Translational Neuroscience,Jing’an District Centre Hospital of Shanghai,Institutes of Brain Science,State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science,Fudan University,Shanghai 200032,China [2]Department of Hand Surgery,Huashan Hospital,Fudan University,Shanghai 200040,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第12期5249-5266,共18页药学学报（英文版）

基　　金：supported by National Natural Science Foundation of China(31930042 and 82021002);STI 2030-Major Projects(2021ZD0203200-5,China)and by funds from the innovative research team of high-level local universities in Shanghai,Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01,China),ZJLab and Shanghai Center for Brain Science and Brain-Inspired Technology.

摘　　要：Spinal microglia and astrocytes are both involved in neuropathic and inflammatory pain,which may display sexual dimorphism.Here,we demonstrate that the sustained activation of spinal astrocytes and astrocyte-derived interleukin(IL)-17A promotes the progression of mouse bone cancer pain without sex differences.Chemogenetic or pharmacological inhibition of spinal astrocytes effectively ameliorates bone cancer-induced pain-like behaviors.In contrast,chemogenetic or optogenetic activation of spinal astrocytes triggers pain hypersensitivity,implying that bone cancer-induced astrocytic activation is involved in the development of bone cancer pain.IL-17A expression predominantly in spinal astro-cytes,whereas its receptor IL-17 receptor A(IL-17RA)was mainly detected in neurons expressing VGLUT2 and PAX2,and a few in astrocytes expressing GFAP.Specific knockdown of IL-17A in spinal astrocytes blocked and delayed the development of bone cancer pain.IL-17A overexpression in spinal astrocytes directly induced thermal hyperalgesia and mechanical allodynia,which could be rescued by CaMKIIa inhibitor.Moreover,selective knockdown IL-17RA in spinal Vglut2^(+)or Vgat^(+)neurons,but not in astrocytes,significantly blocked the bone cancer-induced hyperalgesia.Together,our findings pro-vide evidence for the crucial role of sex-independent astrocytic signaling in bone cancer pain.Targeting spinal astrocytes and IL-17A/IL-17RA-CaMKIIa signaling may offer new gender-inclusive therapeutic strategies for managing bone cancer pain.

关 键 词：ASTROCYTE MICROGLIA INTERLEUKIN-17A Sex difference Chemogenetic manipulation Optogenetic manipulation Bone cancer pain Spinal cord 

分 类 号：R73[医药卫生—肿瘤]