Astrocytes are important components of the innate immune response in the central nervous system (CNS), involving in the inflammatory and neurotoxic responses that occur in CNS diseases, such as multiple sclerosis (MS). Recent studies have shown that SARM1 plays a critical role in axonal degeneration and inflammation. However, the detailed role of astrocytic SARM1 in MS remains unclear. Here, we established the MS model of mice - experimental autoimmune encephalomyelitis (EAE) and found that SARM1 was upregulated in astrocytes of the spinal cords of EAE mice. Moreover, conditional knockout of astrocytic SARM1 (SARM1GFAP-CKO mice, SARM1Aldh1L1-CKO mice) delayed EAE with later onset, alleviated the inflammatory infiltration, and inhibited the demyelination and neuronal death. Mechanically, RNA-seq revealed that the expression of glial-derived neurotrophic factor (GDNF) was upregulated in SARM1−/− astrocytes. Western blot and immunostaining further confirmed the upregulation of GDNF in spinal cord astrocytes of SARM1GFAP-CKO EAE mice. Interestingly, the downregulation of GDNF by streptozotocin (STZ, a drug used to downregulate GDNF) treatment worsened the deficits of SARM1GFAP-CKO EAE mice. These findings identify that astrocytic SARM1 promotes neuroinflammation and axonal demyelination in EAE by inhibiting the expression of GDNF, reveal the novel role of SARM1/GDNF signaling in EAE, and provide new therapeutic ideas for the treatment of MS.
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.
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