%A Xiao,Yifan %A Sun,Yan %A Liu,Wei %A Zeng,FanFan %A Shi,Junyu %A Li,Jun %A Chen,Huoying %A Tu,Chang %A Xu,Yong %A Tan,Zheng %A Gong,Feili %A Shu,Xiji %A Zheng,Fang %D 2021 %J Frontiers in Immunology %C %F %G English %K Sonic Hedgehog (Shh),HMGB1,Astrocytes,Experimental autoimmune encephalomyelitis (EAE),Receptor for advanced glycation end products (RAGE) %Q %R 10.3389/fimmu.2021.584097 %W %L %M %P %7 %8 2021-April-01 %9 Original Research %+ Xiji Shu,Department of Pathology and Pathophysiology, School of Medicine, Jianghan University,China,zhengfangtj@hust.edu.cn %+ Xiji Shu,School of Medicine, Institutes of Biomedical Sciences, Jianghan University,China,zhengfangtj@hust.edu.cn %+ Fang Zheng,Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,China,zhengfangtj@hust.edu.cn %+ Fang Zheng,Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences,China,zhengfangtj@hust.edu.cn %# %! HMGB1 promotes shh release %* %< %T HMGB1 Promotes the Release of Sonic Hedgehog From Astrocytes %U https://www.frontiersin.org/articles/10.3389/fimmu.2021.584097 %V 12 %0 JOURNAL ARTICLE %@ 1664-3224 %X High mobility group box 1 protein (HMGB1) is known to be a trigger of inflammation in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, it may play a different role in some way. Here we investigated the effect of HMGB1 on promoting sonic hedgehog (shh) release from astrocytes as well as the possible signal pathway involved in it. Firstly, shh increased in astrocytes after administration of recombinant HMGB1 or decreased after HMGB1 was blocked when stimulated by homogenate of the onset stage of EAE. Moreover, the expression of HMGB1 receptors, toll-like receptor (TLR) 2 and receptor for advanced glycation end products (RAGE) increased after HMGB1 administration in primary astrocytes. However, the enhancing effect of HMGB1 on shh release from astrocytes was suppressed only after RAGE was knocked out or blocked. Mechanistically, HMGB1 functioned by activating RAGE-mediated JNK, p38, stat3 phosphorylation. Moreover, HMGB1 could induce shh release in EAE. Additionally, intracerebroventricular injection of recombinant shh protein on the onset stage of EAE alleviated the progress of disease and decreased demylination, compared to the mice with normal saline treatment. Overall, HMGB1 promoted the release of shh from astrocytes through signal pathway JNK, p38 and stat3 mediated by receptor RAGE, which may provide new insights of HMGB1 function in EAE.