Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1-/-mouse model.
Severe hyperbilirubinemia is toxic during central nervous system development. Prolonged and uncontrolled high levels of unconjugated bilirubin lead to bilirubin-induced neurological damage and eventually death by kernicterus. Bilirubin neurotoxicity is characterized by a wide array of neurological deficits, including irreversible abnormalities in motor, sensitive and cognitive functions, due to bilirubin accumulation in the brain. Despite the abundant literature documenting the in vitro and in vivo toxic effects of bilirubin, it is unclear which molecular and cellular events actually characterize bilirubin-induced neurodegeneration in vivo.



We used a mouse model of neonatal hyperbilirubinemia to temporally and spatially define the response of the developing cerebellum to the bilirubin insult.



We showed that the exposure of developing cerebellum to sustained bilirubin levels induces the activation of oxidative stress, ER stress and inflammatory markers at the early stages of the disease onset. In particular, we identified TNFα and NFKβ as key mediators of bilirubin-induced inflammatory response. Moreover, we reported that M1 type microglia is increasingly activated during disease progression. Failure to counteract this overwhelming stress condition resulted in the induction of the apoptotic pathway and the generation of the glial scar. Finally, bilirubin induced the autophagy pathway in the stages preceding death of the animals.



This study demonstrates that inflammation is a key contributor to bilirubin damage that cooperates with ER stress in the onset of neurotoxicity. Pharmacological modulation of the inflammatory pathway may be a potential intervention target to ameliorate neonatal lethality in Ugt1-/-mice.
International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 99, 34149, Trieste, Italy.
Simone
S
Vodret
International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 99, 34149, Trieste, Italy. giulia.bortolussi@icgeb.org.
Giulia
G
Bortolussi
Institute of Medical Biochemistry and Laboratory Medicine, First Faculty of Medicine, Charles University, 120 00, Prague, Czech Republic.
Jana
J
Jašprová
Institute of Medical Biochemistry and Laboratory Medicine, First Faculty of Medicine, Charles University, 120 00, Prague, Czech Republic.|Fourth Department of Internal Medicine, First Faculty of Medicine, Charles University, 120 00, Prague, Czech Republic.
Libor
L
Vitek
International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 99, 34149, Trieste, Italy. muro@icgeb.org.
Andrés F
AF
Muro
D000818:Animals; D000831:Animals, Newborn; D002531:Cerebellum / Q000473:pathology*; D004195:Disease Models, Animal; D014453:Glucuronosyltransferase / Q000172:deficiency; D051556:Hyperbilirubinemia, Neonatal / Q000150:complications* / Q000473:pathology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D000099148:UGT1A1 Enzyme
D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme
Apoptosis; Astrocytes; Autophagy; Crigler-Najjar syndrome; ER stress; Microglia; Oxidative stress; Ugt1a1