Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert anti-inflammatory effects relevant to the chronic complications of type 2 diabetes. Although GLP-1RAs attenuate T cell-mediated gut and systemic inflammation directly through the gut intraepithelial lymphocyte GLP-1R, how GLP-1RAs inhibit sy...
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Veröffentlicht in: | Cell metabolism 2024-01, Vol.36 (1), p.130-143.e5 |
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Sprache: | eng |
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Zusammenfassung: | Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert anti-inflammatory effects relevant to the chronic complications of type 2 diabetes. Although GLP-1RAs attenuate T cell-mediated gut and systemic inflammation directly through the gut intraepithelial lymphocyte GLP-1R, how GLP-1RAs inhibit systemic inflammation in the absence of widespread immune expression of the GLP-1R remains uncertain. Here, we show that GLP-1R activation attenuates the induction of plasma tumor necrosis factor alpha (TNF-α) by multiple Toll-like receptor agonists. These actions are not mediated by hematopoietic or endothelial GLP-1Rs but require central neuronal GLP-1Rs. In a cecal slurry model of polymicrobial sepsis, GLP-1RAs similarly require neuronal GLP-1Rs to attenuate detrimental responses associated with sepsis, including sickness, hypothermia, systemic inflammation, and lung injury. Mechanistically, GLP-1R activation leads to reduced TNF-α via α1-adrenergic, δ-opioid, and κ-opioid receptor signaling. These data extend emerging concepts of brain-immune networks and posit a new gut-brain GLP-1R axis for suppression of peripheral inflammation.
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•GLP-1R agonism attenuates TLR-induced inflammation•Semaglutide reduces the severity of polymicrobial inflammation•Anti-inflammatory actions of GLP-1R agonists require CNS GLP-1Rs•GLP-1R agonists reduce inflammation through CNS adrenergic and opioid GPCRs
GLP-1R agonists may reduce cardiometabolic complications in part through reduction of inflammation. Here we show, using pharmacology and genetics, that the anti-inflammatory actions of GLP-1RAs to reduce TLR-mediated inflammation require CNS GLP-1R signaling. |
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ISSN: | 1550-4131 1932-7420 |
DOI: | 10.1016/j.cmet.2023.11.009 |