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NLRP3 at the crossroads between immune/inflammatory responses and enteric neuroplastic remodelling in a mouse model of diet‐induced obesity
Author(s) -
Pellegrini Carolina,
Fornai Matteo,
Benvenuti Laura,
Colucci Rocchina,
Caputi Valentina,
PalazonRiquelme Pablo,
Giron Maria Cecilia,
Nericcio Anna,
Garelli Francesca,
D'Antongiovanni Vanessa,
Segnani Cristina,
Ippolito Chiara,
Nannipieri Monica,
LopezCastejon Gloria,
Pelegrin Pablo,
Haskó György,
Bernardini Nunzia,
Blandizzi Corrado,
Antonioli Luca
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15532
Subject(s) - inflammasome , medicine , endocrinology , inflammation , resistin , diet induced obese , immune system , leptin , adipokine , immunology , obesity , insulin resistance
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. Experimental Approach 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. Key Results HFD mice displayed increased body and epididymal fat weight, cholesterol levels, plasma resistin levels and plasma and colonic IL‐1β 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‐1β release. This effect was inhibited upon incubation with caspase‐1 inhibitor or NK 1 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/NK 1 pathways underlying the onset of colonic dysmotility. Identifying NLRP3 as a therapeutic target for the treatment of bowel symptoms related to obesity.