HMGB1 A Box prevents neuronal injury from PD via restricting activation of microglia and inhibiting differentiation and infiltration of Th17 cells

Abstract

Abstract Parkinson’s disease is a complexly neuronal injury and accompanied by many clinical challenges, for example, lacking of early diagnostic strategies and effective treatment. Here, we demonstrate that in the subacute Parkinson’s disease mice model, injection of HMGB1 competitive inhibitor protein HMGB1 A Box restored the number of dopaminergic neurons and TH+ fibers in the substantia nigra striatum. Our data also showed that A Box inhibited the activation of microglia mediated by neuronal injury and the production of TNF α and IL-1β by up-regulating microglia CD200-CD200R signal axis in vitro and in vivo. Microglia overexpressing CD200R produced fewer inflammatory mediators and restored TH+ neurons in vitro. Intravenous injection of A Box also reduced the levels of RANTES and CXCL12 in substantia nigra and significantly inhibited Th17 cells infiltration. The ability of activated microglia to promote naïve CD4+ T cells differentiation into Th17 in MPP+ model in vitro was also inhibited by A Box. Elevated levels of these two chemokines were also detected in the serum of the patients. In conclusion, our studies show that HMGB1 can induce neuronal damage by activating microglia to promote the production of inflammatory mediators. HMGB1 itself does not directly cause neuronal death. Moreover, the differentiation of T cells into Th17 and migration of T cells secondary to microglia activation induced by HMGB1 further aggravates neuronal damage. The significant effect of HMGB1 A Box indicates the possibility that this recombinant protein might become a potent inhibitor of neuroinflammation in Parkinson’s disease.