NLRP3 at the crossroads between immune/inflammatory responses and enteric neuroplastic remodelling in a mouse model of diet‐induced obesity

• Published in: British journal of pharmacology Vol. 178; no. 19; pp. 3924 - 3942
• Main Authors: Pellegrini, Carolina, Fornai, Matteo, Benvenuti, Laura, Colucci, Rocchina, Caputi, Valentina, Palazon‐Riquelme, Pablo, Giron, Maria Cecilia, Nericcio, Anna, Garelli, Francesca, D'Antongiovanni, Vanessa, Segnani, Cristina, Ippolito, Chiara, Nannipieri, Monica, Lopez‐Castejon, Gloria, Pelegrin, Pablo, Haskó, György, Bernardini, Nunzia, Blandizzi, Corrado, Antonioli, Luca
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-10-2021
• Subjects: Animals; Apoptosis; Caspase; Cholesterol; colonic motility; Diet, High-Fat - adverse effects; Enteric nervous system; Gene expression; High fat diet; Inflammasomes; Inflammation; Intestine; Macrophages; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; NLRP3 inflammasome; Obesity; Signal transduction; Substance P; tachykinin neurotransmission; Therapeutic targets; macrophages; colonic motility; inflammation; high-fat diet; NLRP3 inflammasome; substance P; obesity; tachykinin neurotransmission
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.15532

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 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.