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