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 pro-inflammatory and tissue protective functions. Ongoing studies are examining how particular cell-extrinsic signals (such as cytokines) and cell-intrinsic factors (such as enzymes and solute carriers) control this metabolic reprogramming.
For example, we discovered that the amino acid enzyme Arginase 1 (Arg1) was a constitutive hallmark of the ILC2 lineage and that deletion of Arg1 limited ILC2 proliferation by inhibiting polyamine synthesis and reducing glycolytic capacity, thereby preventing development of airway inflammation. However, whether this enzyme has roles outside the ILC2 lineage is unknown. Unexpectedly, we’ve recently found that Arg1 expression is remarkably heterogeneous across ILC subsets and is dynamically regulated at a tissue-specific level in response to mucosal barrier damage. Expression of Arg1 delineated unique populations within the ILC1 and ILC3 lineages that were transcriptionally and functionally distinct from their Arg1neg counterparts, suggesting that Arg1 enzymatic activity and downstream metabolites may control the ability of distinct ILC subsets to serve either pathologic or tissue-protective roles. Consistent with this, selective genetic deletion of ILC Arg1 in murine models of mucosal injury and infection resulted in reduced pro-inflammatory capacity while leaving the host-beneficial properties of ILCs intact, suggesting that this enzyme is a global instructor of the ILC family that governs pathologic versus tissue-protective roles during tissue damage and inflammation.