A metabolic sensor controls pathologic ILC2 function to regulate airway inflammation

Abstract

Abstract Employing models of allergen exposure, pathogen infection, and chronic inflammation, research in the Monticelli lab is examining how the innate immune system responds to tissue-specific cues to modulate cellular metabolism in order to coordinately regulate resolution of inflammation and promotion of tissue homeostasis at the body’s barrier surfaces. Our recent findings indicate that subsets of innate lymphoid cells (ILCs) utilize distinct metabolic pathways to fuel their proliferation and activation, and that this bioenergetic re-wiring influences their proinflammatory and tissue protective functions. Ongoing studies are examining how particular cell-extrinsic signals (such as cytokines) and cell-intrinsic factors (such as enzymes and transcription factors) control this metabolic reprogramming. In new unpublished studies, we’ve found that lung-resident ILC2s upregulate expression of the metabolic ‘sensor’ transcription factor aryl hydrocarbon receptor (Ahr) upon activation with select airway allergens. Genetic or pharmacologic manipulation of Ahr signaling in murine models directly regulated ILC2 responses during airway inflammation, suggesting that ILC2-intrinsic sensing of Ahr ligand metabolites is critical for protection versus progression of innate immune lung disease pathogenesis.