Microglia-derived IL-1β promoted neuronal apoptosis through ER stress-mediated signaling pathway PERK/eIF2α/ATF4/CHOP upon arsenic exposure

Abstract

Arsenic is the leading toxicant of hazardous environmental chemicals, which is linked with neurotoxicity including cognitive dysfunction, neurodevelopmental alterations and neurodegenerative disorders. It has been suggested that sustained pro-inflammatory response is one of the triggering factors of arsenic-induced neurotoxicity. Microglia, the immune cells in the central nervous system, response to physiological and pathological stress, and release a large array of pro-inflammatory cytokines if activated excessively. Several studies indicated that arsenic was capable of inducing microglia activation, however, the role of the subsequently released pro-inflammatory cytokines in arsenic-induced neurotoxicity remains to be elucidated. Our findings demonstrated that arsenic-induced cognitive dysfunction, microglia activation, up-regulation and release of IL-1β and ER stress-mediated apoptosis could be attenuated by minocycline, a recognized inhibitor of microglia activation. In addition, the IL-1 receptor antagonist IL-1ra diminished arsenic-induced activation of ER stress-mediated apoptotic pathway PERK/eIF2α/ATF4/CHOP and neuronal apoptosis. Our findings provided evidences that arsenic-induced microglia activation also contributed to neuronal apoptosis through pro-inflammatory cytokine. Microglia-derived IL-1β promoted hippocampal neuronal apoptosis through ER stress-mediated PERK/eIF2α/ATF4/CHOP apoptotic pathway. Neuronal apoptosis induced by prolonged activation of microglia was partially involved in the arsenic-induced cognitive dysfunction.