Abstract
Biological and signaling events that connect developmentally induced hyperbilirubinemia to bilirubin-induced neurological dysfunction (BIND) and 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 for bilirubin metabolism and clearance. Humanized mice that express the entire UGT1 locus (hUGT1) and the UGT1A1 gene, develop neonatal hyperbilirubinemia, with 8-10% of hUGT1 mice succumbing to CNS damage, a phenotype that is presented by uncontrollable seizures. We demonstrate that neuroinflammation and reactive gliosis are prominent features of bilirubin brain toxicity, and a disturbed redox status resulting from activation of NADPH oxidase is an important contributing mechanism found in BIND. Using knock-out mice and primary brain cells, we connect a key pattern recognition receptor, Toll-like receptor 2 (TLR2), to hyperbilirubinemia-induced signaling. We illustrate a requirement for TLR2 signaling in regulating gliosis, proinflammatory mediators, and oxidative stress when neonatal mice encounter severe hyperbilirubinemia. TLR2-mediated gliosis strongly correlates with pronounced neuroinflammation in the CNS with up-regulation of TNFα, IL-1β, and IL-6, creating a pro-inflammatory CNS environment. Gene expression and immunohistochemistry staining show that hUGT1/Tlr2(-/-) mice fail to activate glial cells, proinflammatory cytokines, and stress response genes. In addition, bilirubin-induced apoptosis was significantly enhanced by blocking TLR2 signaling indicating its anti-apoptotic property. Consequently, a higher neonatal death rate (57.1%) in hUGT1/Tlr2(-/-) mice was observed when compared with hUGT1 mice (8.7%). These results suggest that TLR2 signaling and microglia neuroinflammation are linked to a repair and/or protection mode against BIND.
Highlights
Neonatal jaundice with dangerously high levels of serum bilirubin leads to neurological toxicity
We demonstrate that neuroinflammation and reactive gliosis are prominent features of bilirubin brain toxicity, and a disturbed redox status resulting from activation of NADPH oxidase is an important contributing mechanism found in bilirubin-induced neurological dysfunction (BIND)
These results suggest that Toll-like receptor 2 (TLR2) signaling and microglia neuroinflammation are linked to a repair and/or protection mode against BIND
Summary
Neonatal jaundice with dangerously high levels of serum bilirubin leads to neurological toxicity. Results: Toll-like receptor 2 signaling is essential for regulation of glia activation, neuroinflammation, and oxidative stress when neonatal mice experience severe hyperbilirubinemia. A higher neonatal death rate (57.1%) in hUGT1/Tlr2؊/؊ mice was observed when compared with hUGT1 mice (8.7%) These results suggest that TLR2 signaling and microglia neuroinflammation are linked to a repair and/or protection mode against BIND. All of the neonatal hUGT1 mice display dramatically elevated levels of total serum bilirubin, a consequence that results from developmentally repressed expression of the liver UGT1A1 gene [6]. The initial discovery of heat shock protein (HSP) 27 induction in brain tissue of BIND mice led us to investigate TLR involvement in bilirubin-mediated toxicity as HSPs have been recognized as damage-associated molecular patterns that are associated with TLR activation [16]. This study sheds an important light on TLR2-dependent neuroinflammation and glial activation as crucial mechanisms in the defensive response to hyperbilirubinemia toxicity
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