Environmental Microcystin exposure in underlying NAFLD-induced exacerbation of neuroinflammation, blood-brain barrier dysfunction, and neurodegeneration are NLRP3 and S100B dependent.
Toxicology
; 461: 152901, 2021 09.
Article
en En
| MEDLINE
| ID: mdl-34416350
ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) has been shown to be associated with extrahepatic comorbidities including neuronal inflammation and Alzheimer's-like pathology. Environmental and genetic factors also act as a second hit to modulate severity and are expected to enhance the NAFLD-linked neuropathology. We hypothezied that environmental microcystin-LR (MC-LR), a toxin produced by harmful algal blooms of cyanobacteria, exacerbates the neuroinflammation and degeneration of neurons associated with NAFLD. Using a mouse model of NAFLD, exposed to MC-LR subsequent to the onset of fatty liver, we show that the cyanotoxin could significantly increase proinflammatory cytokine expression in the frontal cortex and cause increased expression of Lcn2 and HMGB1. The above effects were NLRP3 inflammasome activation-dependent since the use of NLRP3 knockout mice abrogated the increase in inflammation. NLRP3 was also responsible for decreased expression of the blood-brain barrier (BBB) tight junction proteins Occludin and Claudin 5 suggesting BBB dysfunction was parallel to neuroinflammation following microcystin exposure. An increased circulatory S100B release, a hallmark of astrocyte activation in MC-LR exposed NAFLD mice also confirmed BBB integrity loss, but the astrocyte activation observed in vivo was NLRP3 independent suggesting an important role of a secondary S100B mediated crosstalk. Mechanistically, conditioned medium from reactive astrocytes and parallel S100B incubation in neuronal cells caused increased inducible NOS, COX-2, and higher BAX/ Bcl2 protein expression suggesting oxidative stress-mediated neuronal cell apoptosis crucial for neurodegeneration. Taken together, MC-LR exacerbated neuronal NAFLD-linked comorbidities leading to cortical inflammation, BBB dysfunction, and neuronal apoptosis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Barrera Hematoencefálica
/
Microcistinas
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Enfermedad del Hígado Graso no Alcohólico
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Proteína con Dominio Pirina 3 de la Familia NLR
/
Toxinas Marinas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Toxicology
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
IE
/
IRELAND
/
IRLANDA