NLRP3 at the crossroads between immune/inflammatory responses and enteric neuroplastic remodelling in a mouse model of diet-induced obesity.
Br J Pharmacol
; 178(19): 3924-3942, 2021 10.
Article
em En
| MEDLINE
| ID: mdl-34000757
ABSTRACT
BACKGROUND AND PURPOSE:
Enteric neurogenic/inflammation contributes to bowel dysmotility in obesity. We examined the role of NLRP3 in colonic neuromuscular dysfunctions in mice with high-fat diet (HFD)-induced obesity. EXPERIMENTALAPPROACH:
Wild-type C57BL/6J and NLRP3-KO (Nlrp3-/- ) mice were fed with HFD or standard diet for 8 weeks. The activation of inflammasome pathways in colonic tissues from obese mice was assessed. The role of NLRP3 in in vivo colonic transit and in vitro tachykininergic contractions and substance P distribution was evaluated. The effect of substance P on NLRP3 signalling was tested in cultured cells. KEYRESULTS:
HFD mice displayed increased body and epididymal fat weight, cholesterol levels, plasma resistin levels and plasma and colonic IL-1ß levels, colonic inflammasome adaptor protein apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC) and caspase-1 mRNA expression and ASC immunopositivity in macrophages. Colonic tachykininergic contractions were enhanced in HFD mice. HFD NLRP3-/- mice developed lower increase in body and epididymal fat weight, cholesterol levels, systemic and bowel inflammation. In HFD Nlrp3-/- mice, the functional alterations of tachykinergic pathways and faecal output were normalized. In THP-1 cells, substance P promoted IL-1ß release. This effect was inhibited upon incubation with caspase-1 inhibitor or NK1 antagonist and not observed in ASC-/- cells. CONCLUSION AND IMPLICATIONS In obesity, NLRP3 regulates an interplay between the shaping of enteric immune/inflammatory responses and the activation of substance P/NK1 pathways underlying the onset of colonic dysmotility. Identifying NLRP3 as a therapeutic target for the treatment of bowel symptoms related to obesity.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína 3 que Contém Domínio de Pirina da Família NLR
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Obesidade
Limite:
Animals
Idioma:
En
Revista:
Br J Pharmacol
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Itália