Glial A2B Adenosine Receptors Modulate Abnormal Tachykininergic Responses and Prevent Enteric Inflammation Associated with High Fat Diet-Induced Obesity

Abstract

The role played by adenosine A2B receptors (A2BRs) in the regulation of enteric glial cell (EGC) functions remains unclear. This study was aimed at investigating the involvement of A2BRs in the control of EGC functions in a model of obesity. C57BL/6 mice were fed with standard diet (SD) or high fat diet (HFD) for eight weeks. Colonic tachykininergic contractions were recorded in the presence of BAY60-6583 (A2BRs agonist), MRS1754 (A2BRs antagonist), and the gliotoxin fluorocitrate. Immunofluorescence distribution of HuC/D, S100β, and A2BRs was assessed in whole mount preparations of colonic myenteric plexus. To mimic HFD, EGCs were incubated in vitro with palmitate (PA) and lipopolysaccharide (LPS), in the absence or in the presence of A2BR ligands. Toll-like receptor 4 (TLR4) expression was assessed by Western blot analysis. Interleukin-1β (IL-1β), substance P (SP), and glial cell derived neurotrophic factor (GDNF) release were determined by enzyme-linked immunosorbent assay (ELISA) assays. MRS1754 enhanced electrically evoked tachykininergic contractions of colonic preparations from HFD mice. BAY60-6583 decreased the evoked tachykininergic contractions, with higher efficacy in HFD mice. Such effects were blunted upon incubation with fluorocitrate. In in vitro experiments on EGCs, PA and LPS increased TLR4 expression as well as IL-1β, GDNF, and SP release. Incubation with BAY60-6583 reduced TLR4 expression as well as IL-1β, GDNF, and SP release. Such effects were blunted by MRS1754. The present results suggest that A2BRs, expressed on EGCs, participate in the modulation of enteric inflammation and altered tachykininergic responses associated with obesity, thus representing a potential therapeutic target.

Managing Obesity and Related Comorbidities: A Potential Pharmacological Target in the Adenosine System?

“…In particular, Antonioli et al observed that adenosine, via A 2B Rs, participates to obesity-related enteric dysmotility, modulating the activity of excitatory tachykininergic nerves in HFD mice ( Antonioli et al, 2017 ). In support of this finding, a recent study confirmed the contribution of A 2B Rs, expressed on enteric glial cells, in the modulation of tachykininergic responses and enteric inflammation associated with obesity, thus corroborating the relevant contribution of A 2B Rs to the pathophysiology of bowel motor dysfunctions and inflammation associated with obesity ( D’Antongiovanni et al, 2020c ). Based on these data, the pharmacological modulation of A 2B R represents a viable way to design novel tools to manage both bowel motor dysfunctions and enteric inflammation associated with obesity.…”

Palmitoylethanolamide Counteracts Enteric Inflammation and Bowel Motor Dysfunctions in a Mouse Model of Alzheimer’s Disease

“…Based on these premises, the aims of the present study were: 1) to investigate the putative effect of PEA in curbing enteric inflammatory processes and improving gut dysmotility in a mouse model of AD and 2) to evaluate, via in vitro experiments, the ability of PEA in modulating the activation of EGCs, pivotally involved in the pathophysiology of enteric motor dysfunctions associated with inflammatory conditions ( Delvalle et al, 2018 ; Antonioli et al, 2020 ; D’Antongiovanni et al, 2020a ).…”

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

“…The contractile activity of colonic longitudinal smooth muscle was recorded as described previously (Antonioli et al, 2011(Antonioli et al, , 2017D'Antongiovanni, Benvenuti, et al, 2020). After killing, the colon was removed and placed in cold Krebs solution.…”