SARM1 promotes the neuroinflammation and demyelination through IGFBP2/NF-κB pathway in experimental autoimmune encephalomyelitis mice.

Jingjing Zhang, Lingting Jin, Xin Hua, Mianxian Wang, Jiaojiao Wang, Xingxing Xu, Huitao Liu, Haoyu Qiu, Huankun Sun, Tianyingying Dong, Danlu Yang, Xu Zhang, Ying Wang, Zhihui Huang

Acta physiologica (Oxford, England) 2023 Jun

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Multiple sclerosis (MS) is an autoimmune disease, and its typical characteristics are neuroinflammation and the demyelination of neurons in the central nervous system (CNS). Sterile alpha and TIR motif containing 1 (SARM1) is an essential factor mediating axonal degeneration and SARM1 deletion reduces the neuroinflammation in spinal cord injury. This study aimed to explore the roles of SARM1 and its underlying mechanisms in MS. Experimental autoimmune encephalomyelitis (EAE, a model of MS) model was established. Immunostaining, western blot, electron microscope, and HE staining were used to examine the pathological manifestations such as inflammation, demyelination, and neuronal death in SARM1f/f EAE mice and SARM1Nestin -CKO EAE mice. In addition, RNA-seq, real-time PCR and double-immunostaining were used to examine the underlying mechanism of SARM1 in EAE mice. SARM1 was upregulated in neurons of the spinal cords of EAE mice. SARM1 knockout in CNS ameliorated EAE with less neuroinflammation, demyelination, and dead neurons. Mechanically, SARM1 knockout resulted in the reduction of insulin-like growth factor (IGF)-binding protein 2 (IGFBP2) in neurons of EAE mice, which might inhibit the neuroinflammation through inhibiting NF-κB signaling. Finally, activation of NF-κB partially aggravated the neuroinflammation and demyelination deficits of SARM1Nestin -CKO EAE mice. These results identified the unknown role of SARM1 in the promotion of neuroinflammation and demyelination and revealed a novel drug target pathway of SARM1/IGFBP2/NF-κB for MS. © 2023 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Citation

Jingjing Zhang, Lingting Jin, Xin Hua, Mianxian Wang, Jiaojiao Wang, Xingxing Xu, Huitao Liu, Haoyu Qiu, Huankun Sun, Tianyingying Dong, Danlu Yang, Xu Zhang, Ying Wang, Zhihui Huang. SARM1 promotes the neuroinflammation and demyelination through IGFBP2/NF-κB pathway in experimental autoimmune encephalomyelitis mice. Acta physiologica (Oxford, England). 2023 Jun;238(2):e13974