MCC950 Alleviates Experimental Autoimmune Neuritis by Inhibiting NLRP3 Inflammasome Activity and Down-Regulating Interleukin-23/Interleukin-17 Axis Expression

Yi Li,1 Xiaocong Li,1 Tao Gu,2 Li Wang,2 Man Song,2 Liping Yang,2 Qinghua Huang,3 Juan Yang1 1Department of Neurology, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China; 2Ningxia Medical University, Yinchuan, People’s Republic of China; 3Emergency department, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of ChinaCorrespondence: Qinghua Huang, Emergency Department, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China, Email [email protected] Juan Yang, Department of Neurology, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China, Email [email protected]: Guillain-Barré syndrome (GBS), an autoimmune disease involving the peripheral nervous system, is the most common and severe acute paralytic neuropathy. However, the exact pathogenesis remains unclear. The aim of this study was to reveal the role of the NLRP3 inflammasome in regulating the Interleukin-23/Interleukin-17 axis (IL-23/IL-17 axis) in experimental autoimmune neuritis (EAN) and to explore the potential of the NLRP3 inflammasome as a drug target for the treatment of GBS.Methods: We first evaluated the expression of NLRP3 inflammasome-related genes in peripheral blood mononuclear cells (PBMCs) of GBS patients using real-time quantitative polymerase chain reaction (qPCR). Subsequently, MCC950, a NLRP3 inflammasome inhibitor, was used to detect its therapeutic effect on EAN rats induced by P257-71 peptide immunization. The expression of NLRP3 inflammasome mRNA in the sciatic nerve was detected by qPCR, and the changes of NLRP3 inflammasome and IL-23/IL-17 axis related proteins were evaluated by Western blotting (WB) and immunofluorescence (IF). The effect of MCC950 on EAN peripheral nerve injury and its potential mechanism were evaluated in multiple dimensions through clinical symptom scoring, neuroelectrophysiological examination and IF.Results: We observed that the expression of NLRP3 inflammasome related genes was increased in the peripheral blood of patients with GBS. In the EAN rat model, inhibition of NLRP3 inflammasome with MCC950 not only alleviated neurological symptoms, decreased peripheral nerve CD4+ T cell and macrophage infiltration, but also ameliorated peripheral nerve conduction disorders and mitigated myelin loss. Mechanically, the potential protective effect of MCC950 on EAN might realized via inhibiting the NLRP3 inflammasome signaling pathway and down-regulating the expression of IL-23/IL-17 axis.Conclusion: In the study, we demonstrated that NLRP3 inflammasome is involved in the injury of experimental autoimmune neuritis by up-regulating the expression of IL-23/IL-17 axis. This discovery provides strong evidence for the NLRP3 inflammasome as a drug target for GBS.Keywords: NLRP3 inflammasome, interleukin-23/interleukin-17 axis, experimental autoimmune neuritis, MCC950