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 1b, IL 18, IL 33) IL 25, and TNF superfamilies (TNF, TL1A, GITR L, RANK L) activate the NF kB 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 b2 adrenergic receptor agonists, PGE2, and PGI2 occurs through cAMP and PKA. Glucocorticoid, testosterone, IL 10, and TGF b 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.
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