The cGAS-STING-interferon regulatory factor 7 pathway regulates neuroinflammation in Parkinson’s disease

Abstract

Interferon regulatory factor 7 plays a crucial role in the innate immune response. However, whether interferon regulatory factor 7-mediated signaling contributes to Parkinson’s disease remains unknown. Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–induced mouse model of Parkinson’s disease and co-localizes with microglial cells. Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype. In addition, siRNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase, tumor necrosis factor α, CD16, CD32, and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1. Taken together, our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase–stimulator of interferon genes–interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson’s disease

Keywords

• cyclic guanosine monophosphate adenosine monophosphate synthase
• h151
• interferon regulatory factor 7
• m1 phenotype
• neurodegenerative disease
• neuroinflammation
• parkinson’s disease
• ru521
• sting
• type i interferon