Group 2 Innate Lymphoid Cells in Airway Diseases

Group 2 innate lymphoid cells (ILC2s) are increasingly recognized as a key controller of type 2 inflammation, and are well known to be highly elevated in human airway type 2 inflammatory diseases including allergic rhinitis, chronic rhinosinusitis with nasal polyps, and asthma. ILC2-mediated production of type 2 cytokines initiates and amplifies airway inflammation via activation of eosinophils, B cells, mast cells, macrophages, fibroblasts, and epithelial cells in these diseases. ILC2s require at least three major signals to fully activate and robustly produce type 2 cytokines. IL-1 family cytokines (IL-1β, IL-18, IL-33), IL-25, and TNF superfamilies (TNF, TL1A, GITR-L, RANK-L) activate the NF-κB and AP-1 pathways that initiate production of IL-5 and IL-13. Lipid mediators (LTC₄, LTD₄, PGD₂) and neuropeptide NMU promote production of IL-4 through the NFAT pathway. IL-2 and IL-7 family cytokines (IL-2, IL-7, IL-9, TSLP) activate the STAT5 pathway that induces survival of ILC2s and enhances cytokine production. The activation of STAT5 is necessary to potently induce cytokine- and lipid mediator-mediated production of type 2 cytokines. Inhibitory pathways for ILC2s have also become clearer. Type I and II interferons and IL-27 inhibit ILC2 functions through the activation of STAT1. Suppression mediated via β₂-adrenergic receptor agonists, PGE₂, and PGI₂ occurs through cAMP and PKA. Glucocorticoid, testosterone, IL-10, and TGF-β are also able to inhibit ILC2-mediated production of type 2 cytokines. Blockage of ILC2 activators, activation of inhibitory pathways of ILC2s, and suppression of ILC2-mediated pathways including type 2 cytokines (IL-5, IL-13, IL-4Ra) may become therapeutic strategies for airway type 2 inflammatory diseases.