Direct Activation of Toll-like Receptor 4 Signaling in Group 2 Innate Lymphoid Cells Contributes to Inflammatory Responses of Allergic Diseases

Group 2 innate lymphoid cells (ILC2) play a critical role in type 2 immunity. Although their classical activators are known to be host epithelial-derived alarmin cytokines released from tissue damage at barrier sites during microbial infections and allergen exposures, it remains elusive whether ILC2 cells can be directly activated by microbial ligands. Here we examined a number of microbial ligands and identified lipopolysaccharides (LPS) from multiple species of Gram-negative bacteria potently stimulated the cultured human ILC2 to proliferate and produce massive amounts of type 2 effector cytokines IL-5 and IL-13. RNA-seq data revealed a remarkably similar set of type 2 immune responsive genes induced by LPS and IL-33. However, blocking IL-33 receptor signaling failed to decrease the effects of LPS. In contrast, blocking TLR4 receptor, NF-kB and JAK pathways completely abolished the growth and function of LPS-treated human ILC2. Furthermore, ILC2 cells of TLR4 deficient mice were unable to respond to LPS treatment in vitro and in vivo. Importantly, patients with allergic rhinitis, atopic dermatitis and bacteremia had an increased number of peripheral blood ILC2 cells that correlated with elevated serum endotoxin. Collectively, these findings support a non-canonical mode of direct activation of human ILC2 cells via the LPS-TLR4-NF-kB/JAK signaling axis, which is independent of the classical IL-33-ST2 pathway. Thus, targeting TLR4 signaling pathway might be developed as an alternative approach to treat microbial infection-associated and ILC2-mediated inflammatory conditions.