Chronic Microcystin-LR-Induced α-Synuclein Promotes Neuroinflammation Through Activation of the NLRP3 Inflammasome in Microglia

Microcystin-LR (MC-LR) has been confirmed to cause blood-brain barrier disruption and enter the brain tissue, resulting in non-negligible toxic effects. However, the neurotoxicity of MC-LR is mainly unknown. This study revealed that MC-LR disrupted the function of the ubiquitin-proteasome system in neurons, which inhibited the degradation of alpha-synuclein (alpha-syn), leading to its release from neurons for transport into microglia. alpha-Syn is the main component of Lewy bodies, which has been identified as one of the main pathological features of Parkinson's disease (PD). In vitro, we observed that alpha-syn mediated by MC-LR activated HMC3 cells and polarized them towards M1 type. In addition, we confirmed that alpha-syn was transported into HMC3 cells through TLR4 receptors and activated the NLRP3 inflammasome, which in turn enhanced the maturation and release of IL-18 and IL-1 beta. In the mouse models of chronic MC-LR exposure, a large number of inflammatory factors (IL-6, IL-1 beta, and TNF-alpha) were deposited in brain tissue, and activation of NLRP3 in microglia was also observed in the midbrain. Collectively, MC-LR exposure promoted the pathological spread of alpha-syn from cell to cell, activated NLRP3 inflammasome in microglia, and generated neuroinflammation, in which the TLR4 receptor played a substantial effect.