Innate lymphoid cells (ILCs) are a recently identified population of hematopoietic cells that bridge innate and adaptive immunity. In the lung, a subset of ILCs, ILC2s which express the transcription factor GATA3, rapidly respond to IL-25, thymic stromal lymphopoietin (TSLP) and IL-33, cytokines produced by damaged or stressed airway epithelial cells. This cytokine-induced activation of ILC2s results in the production of IL-5 and IL-13, cytokines important for the expansion of eosinophils and alternative (M2) macrophage activation. As IL-5, IL-13, eosinophilia and M2 polarization are all hallmarks of allergic lung inflammation, ILC2s represent an important therapeutic target for treating pulmonary inflammatory diseases. Recently, our group reported that ILC2 development and function is severely impaired in the absence of the methyltransferase G9a and others have reported that NF-κB transcription factors were added to the list of G9a binding proteins, with G9a found to interact with the NF-κB family members NF-κB1, RelA, c-Rel and RelB in a proteomic screen.
We therefore hypothesized that the canonical NF-κB family member c-Rel has a critical, non-redundant role in ILC2 development, differentiation and function.
Our results show that ex vivo generated ILC2s respond to IL-33 via c-Rel, as determined by EMSA. Analysis of c-Rel KO mice show normal frequencies of ILC2s in the bone marrow and lungs, demonstrating that c-Rel is dispensable for ILC2 development and homeostasis. However, when intranasally challenged with IL-33, c-Rel KO mice show decreased expansion of ILC2s in the lung and less expression of IL-5 and IL-13. In two different models of airway inflammation (papain and HDM) c-Rel KO mice show less eosinophilia compared to WT mice, thus demonstrating the importance of c-Rel in lung inflammation.
Taken together, we show that c-Rel has important functions maintaining the inflammatory character of ILC2s.