HMGB1 Mediates Paraquat-Induced Neuroinflammatory Responses via Activating RAGE Signaling Pathway

Paraquat (PQ), a widely characterized neurotoxicant, has been generally accepted as one of the environmental factors in the etiology of Parkinson's disease (PD). Despite the direct evidence that PQ could induce inflammatory responses in central nervous system, the putative adverse effects of PQ on the neuroimmune interactions have rarely been investigated. High-mobility group box 1 (HMGB1) has been proven to be relevant to the neuroinflammation involved in PD; however, whether and how HMGB1 exerts modulatory effects in nervous system upon PQ exposure remain elusive. Therefore, the present study investigated the underlying association between HMGB1 and PQ exposure in SH-SY5Y cells, which is a well-established in vitro model for PD research. We observed that HMGB1 was markedly increased in a concentration and time-dependent manner upon PQ exposure, and the elevated HMGB1 could be translocated into cytosol and then released to the extracellular milieu of SH-SY5Y cells. Knockdown of HMGB1 inhibited the activation of RAGE-P38-NF-κB signaling pathway and the expression of inflammation cytokines such as TNF-α and IL-6. These results suggested that HMGB1 is involved in the PQ-induced neuron death via activating RAGE signaling pathways and promoting neuroinflammatory responses.