Fig. 4: The influence of diet/diet-derived metabolites and microbial ligands on ILC2 activity.

a A fiber-rich diet can increase SCFA-producing gut microbes. In particular, the SCFA butyrate negatively regulates ILC2 functions through HDAC inhibition, which suppresses the expression of GATA3 and its downstream genes, including Il13 and Il5. The glucose-deprived ketogenic diet attenuates ILC2 functions by inhibiting FAO (see Fig. 3, pathways 3 and 4 for a detailed mechanism). The ketogenic diet also increases the ketone body BHB. BHB can attenuate ILC2 functions by suppressing IL-2 production by mast cells via GPR109a. b Exposure to microbial ligands activates TLRs, which can directly or indirectly influence lung ILC2 activity. TLR2 acts directly on ILC2s to stimulate cytokine production by activating the transcription factors AP-1 and NF-κB. In contrast, activation of endosomal TLRs (TLR3, TLR7, and TLR9) on myeloid cells negatively regulates ILC2 functions through IFNs and IL-27 in a STAT1-dependent manner. The activation of TLR3 and TLR7 on CD8α⁺ DCs and plasmacytoid DCs, respectively, induces type I IFN production, which inhibits ILC2s through IFNAR signaling. Plasmacytoid DCs also express TLR9, and the activation of TLR9 by unmethylated CpG DNA triggers type I IFN production, which in turn stimulates IFN-γ-producing NK cells to suppress ILC2s through IFNGR. Moreover, TLR7 activation on interstitial macrophages induces IL-27 production, which negatively regulates ILC2s via IL-27R signaling. The full term for each abbreviation can be found in the text.