Are ILC2s Jekyll and Hyde in airway inflammation?
Asthma is a complex heterogeneous disease of the airways characterized by lung inflammation, airway hyperreactivity (AHR), mucus overproduction, and remodeling of the airways. Group 2 innate lymphoid cells (ILC2s) play a crucial role in the initiation and propagation of type 2 inflammatory programs in allergic asthma models, independent of adaptive immunity. In response to allergen, helminths or viral infection, damaged airway epithelial cells secrete IL-33, IL-25, and thymic stromal lymphopoietin (TSLP), which activate ILC2s to produce type 2 cytokines such as IL-5, IL-13, and IL-9. Furthermore, ILC2s coordinate a network of cellular responses and interact with numerous cell types to propagate the inflammatory response and repair lung damage. ILC2s display functional plasticity in distinct asthma phenotypes, enabling them to respond to very different immune microenvironments. Thus, in the context of non-allergic asthma, triggered by exposure to environmental factors, ILC2s transdifferentiate to ILC1-like cells and activate type 1 inflammatory programs in the lung. In this review, we summarize accumulating evidence on the heterogeneity, plasticity, regulatory mechanisms, and pleiotropic roles of ILC2s in allergic inflammation as well as mechanisms for their suppression in the airways.