The cGAS-STING-mediated NLRP3 inflammasome is involved in the neurotoxicity induced by manganese exposure

Abstract

Heavy metal pollution has become a global health challenge. Exposure to heavy metals represents a major health risk. Manganese (Mn) is an essential trace element but also an environmental pollutant. Mn exposure can induce neurotoxicity and lead to neurodegenerative disease. Inflammation and Tau hyperphosphorylation are prominent hallmarks of neurodegenerative diseases induced by Mn exposure. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway can induce powerful innate immune defense programmes and has emerged as a key mediator of inflammation. In recent years, Mn²⁺ has been found to be the second activator of the cGAS-STING pathway in addition to double-stranded DNA (dsDNA). NLRP3 activation is upstream of Tau pathology, and NLRP3 activation induces Tau hyperphosphorylation and aggregation. Mn exposure-induced neurotoxicity may be associated with excessive activation of the cGAS-STING signaling pathway, leading to inflammation. The cGAS-STING/NLRP3 axis may be a promising option for revealing the mechanisms of neurotoxicity of Mn exposure in the future.

Keywords: CGAS-STING; Inflammation; Manganese; NLRP3; Neurotoxicity.