Microcystin‐LR Exacerbates Neuroinflammation and Neurodegeneration in Nonalcoholic Fatty Liver Disease

Abstract

Growing evidence, including findings from our laboratory strongly implicated the effect of environmental pollutants on the progression of Nonalcoholic Fatty Fiver disease (NAFLD) or Nonalcoholic steatohepatitis (NASH) pathology. Microcystin (MC) is one such environmental toxin secreted from harmful, bloom-forming cyanobacteria and is responsible for hepatotoxic and carcinogenic activities. Studies also show that worldwide climate change results in an increased abundance of cyanobacteria and their toxins such as MC and has the potential to become a serious public health threat. Although, MC is known for its hepatotoxicity but recent studies including our research showed MC exposure leads to several ectopic manifestations such as neurotoxicity and intestinal inflammation. Previously we showed intraperitoneal administration of MC-LR exacerbates the risk of Inflammatory bowel disease (IBD) in NAFLD by activation of NLRP3 inflammasome in the intestinal epithelial cells. In the present study we show that intraperitoneal administration of MC-LR (10 µg/Kg) for 5days, also worsened neuroinflammation through NLRP3 inflammasome activation. MC-LR exposure induced expression of pro-inflammatory cytokines TNFα, IL1β and IL 6 in hippocampus and pre-frontal cortex region of the brain, and exacerbated blood brain barrier (BBB) disruption by degradation of tight junction proteins Claudin 5 and Zonula Occludens (ZO1). The BBB disruption was primarily through an increased expression of matrix metallo proteases (MMPs) MMP 2 and MMP 9. Furthermore, results showed that MC-LR exposure resulted in an increased expression of calcium binding protein S100B in the cortex of NAFLD mouse group independent to NLRP3 inflammasome. Increased S100B results in neuronal injury by inducing Cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and neuronal apoptosis through RAGE dependent pathway, leading to neurodegeneration by increasing abundance of phosphorylated Tau protein and decreased BDNF expression. In conclusion the present study strongly implicated MC-LR exposure for a potential increased risk of neuroinflammatory and neurovegetative disorders in NAFLD.