Fig. 1

Modulation of ILC function in asthma. A ILC2 activation is influenced by cytokines and other mediators. IL-33, TSLP, and IL-25 are primary activators, while IL-2, IL-7, IL-9, IL-4, and TNF superfamily members act as co-factors. Meanwhile, type I/II IFNs, IL-27, and IL-10 inhibit ILC2s. Activation leads to GATA3 and NF-κB phosphorylation, driving IL-13 and IL-5 production, proliferation, and survival. IL-1β, IL-12, and IL-18 promote ILC1-like differentiation, marked by IFN-γ production and T-bet expression, while IL-1β, IL-23, and TGF-β drive polarization into IL-17A-producting ILC3-like cells. Notably, IL-4 counteracts these effects. Non-cytokine regulators, including neuropeptides (NMU, VIP, CGRP), prostaglandins (PGI2, PGE2, PGD2), and leukotrienes, can either inhibit or enhance ILC2 activation. Butyrate inhibits ILC2s via HDAC suppression, while BHB indirectly suppresses ILC2s by limiting IL-2 from mast cells. Tregs (ICOS-ICOSL) and SLAMF receptors inhibit ILC2s, while Pla2g5⁺ macrophages (FFAs, IL-33) activate ILC2s. ILC2s also influence CD4⁺ T cells via BTN2A2, PD-L1, and OX40L, promoting Th2 differentiation. Notably, GATA3-expressing Tregs inhibit OX40L expression on ILC2s. B Resolvin-E1 promotes NK cell migration and enhances cytotoxic abilities, while lipoxin A4 promotes eosinophil apoptosis and clearance, together boosting pro-resolving functions of NK cells. In contrast, cannabinoids and PGI2 inhibit IFN-γ production by NK cells, subsequently attenuating ILC2 function. Type I IFNs from pDCs drive NK cell IFN-γ production. NK cell pathogenicity involves TLR3-induced IL-17A production, worsening asthma. NKG2D⁺ NK cells, via MULT-1, elevate IgE and eosinophil levels, promoting allergic airway inflammation. C ILC3s drive neutrophilic inflammation via IL-17. Cigarette smoke induces IL-1β from airway epithelium, generating memory-like ILC3s that worsen neutrophilic asthma. Conversely, MHC-II engagement on ILC3s inhibits microbe-specific Th17 and allergen-specific Th2 cells, reducing neutrophilic and eosinophilic asthma, respectively. NCR⁺ ILC3s interact with the microbiome to enhance protective functions via an unknown mechanism