Developmental onset of bilirubin-induced neurotoxicity involves Toll-like receptor 2-dependent signaling in humanized UDP-glucuronosyltransferase1 mice.

摘要: Biological and signaling events that connect developmentally induced hyperbilirubinemia to bilirubin-induced neurological dysfunction (BIND) CNS toxicity in humans are poorly understood. In mammals, UDP-glucuronosyltransferase 1A1 (UGT1A1) is the sole enzyme responsible for bilirubin glucuronidation, a rate-limiting step necessary metabolism clearance. Humanized mice express entire UGT1 locus (hUGT1) UGT1A1 gene, develop neonatal hyperbilirubinemia, with 8–10% of hUGT1 succumbing damage, phenotype presented by uncontrollable seizures. We demonstrate neuroinflammation reactive gliosis prominent features brain toxicity, disturbed redox status resulting from activation NADPH oxidase an important contributing mechanism found BIND. Using knock-out primary cells, we key pattern recognition receptor, Toll-like receptor 2 (TLR2), hyperbilirubinemia-induced signaling. illustrate requirement TLR2 regulating gliosis, proinflammatory mediators, oxidative stress when encounter severe hyperbilirubinemia. TLR2-mediated strongly correlates pronounced up-regulation TNFα, IL-1β, IL-6, creating pro-inflammatory environment. Gene expression immunohistochemistry staining show hUGT1/Tlr2−/− fail activate glial cytokines, response genes. addition, apoptosis was significantly enhanced blocking indicating its anti-apoptotic property. Consequently, higher death rate (57.1%) observed compared (8.7%). These results suggest microglia linked repair and/or protection mode against