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

Abstract

Aim 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. Methods 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. Results 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. Conclusions 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.

Genetic ablation of Sarm1 attenuates expression and mislocalization of phosphorylated TDP-43 after mouse repetitive traumatic brain injury

“…Limited data indicate that glial activation may precede TDP-43 mislocalization and accumulation [ 49 ] and disease-causing mutations in microglia promote TDP-43 aggregation and cell death, suggesting that TDP-43 proteinopathy and neurodegeneration are interlinked with chronic microglial activation [ 89 ]. In addition to its involvement in axon degeneration, SARM1 plays a key role in innate immunity and inhibition of SARM1 has been shown to attenuate microgliosis in multiple disease models [ 43 , 76 , 90 ] including TBI [ 2 , 15 , 52 ]. Importantly, genetic ablation of Sarm1 prevented axonal degeneration in the spinal cord tracts and the accompanying neuroinflammatory response that extended into the subacute phase after TBI [ 2 ].…”