Blocking CXC Motif Chemokine Ligand 2 Ameliorates Diabetic Peripheral Neuropathy via Inhibiting Apoptosis and NLRP3 Inflammasome Activation.

Abstract

Evidence suggests that CXC motif chemokines are involved in neuronal injury and inflammatory processes. Bioinformatics analysis by using data from the Gene Expression Omnibus (GEO) database was performed and identified CXC motif chemokine ligands (CXCLs) as associated with diabetic peripheral neuropathy (DPN). The present study focused on CXC motif chemokine ligand 2 (CXCL2), and the role and potential mechanisms of CXCL2 in DPN were investigated. The DPN rat model was generated by streptozotocin (STZ) injection in vivo, and high-glucose (HG)-stimulated Schwann cell RSC96 was considered a cell model of DPN in vitro. Neuropathic symptoms of DPN were explored by neurological tests and histological examinations. DPN rats showed a decreased level of motor nerve conduction velocity (MNCV) along with typical histological changes. CXCL2 expression was significantly increased in STZ-induced DPN rat sciatic nerve and HG-induced RSC96 cells. Functionally, CXCL2 knockdown inhibited cell apoptosis and inflammation activation under diabetic conditions in vitro and in vivo. CXCL2 knockdown increased cell viability in HG-treated RSC96 cells and reduced apoptosis concerning the decreased expression of cleaved Caspase 3/9. In addition, CXCL2 knockdown protected against NOD-like receptor protein 3 (NLRP3) inflammasome activation and reduced levels of pro-inflammatory cytokines, interleukin (IL)-1β and IL-18. The repressive effects of CXCL2 knockdown on inflammasome activation under HG conditions were significantly abolished by treatment of the NLRP3 activator nigericin. In conclusion, these results indicated that CXCL2 knockdown exhibited amelioration of hyperglycemia-induced DPN by inhibiting cell apoptosis and NLRP3 inflammasome activation, suggesting that targeting CXCL2 might be a potential strategy for DPN treatment.