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.

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

Pellegrini, Carolina
Primo
;
Fornai, Matteo
Secondo
;
Benvenuti, Laura;D'Antongiovanni, Vanessa;Segnani, Cristina;Ippolito, Chiara;Nannipieri, Monica;Bernardini, Nunzia;Antonioli, Luca
Ultimo
2021-01-01

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. 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.
2021
Pellegrini, Carolina; Fornai, Matteo; Benvenuti, Laura; Colucci, Rocchina; Caputi, Valentina; Palazon-Riquelme, Pablo; Giron, Maria Cecilia; Nericcio,...espandi
File in questo prodotto:
File Dimensione Formato  
Pellegrini et al., 2021 NLRP3 BJP.pdf

non disponibili

Tipologia: Versione finale editoriale
Licenza: Creative commons
Dimensione 4.61 MB
Formato Adobe PDF
4.61 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1102716
Citazioni
  • ???jsp.display-item.citation.pmc??? 4
  • Scopus 11
  • ???jsp.display-item.citation.isi??? 10
social impact