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.
Keywords: Apoptosis; Arsenic; Endoplasmic reticulum stress; IL-1β; Microglia.
Copyright © 2021 Elsevier B.V. All rights reserved.