The IL-33-ILC2 axis: a key regulator of type 2 immunity in respiratory disease

Respiratory diseases represent a major global public health burden, and type 2 immunity plays a key role in their pathogenesis. The interleukin-33 (IL-33)-group 2 innate lymphoid cell (ILC2) axis regulates airway type 2 immune responses, thereby triggering, amplifying, and maintaining pathological inflammation. This review addresses the characteristics of IL-33 and pulmonary ILC2s, including the alarmin function and tissue-specific expression of IL-33, and the origin, localization, functional heterogeneity, and microenvironment-driven plasticity of ILC2s. In particular, we discuss how disease-specific microenvironments shape divergent ILC2 states, including classical type 2 cytokine-producing ILC2s, tissue-repairing AREG-producing ILC2s, ILC1-like cells, and IL-17-producing ILC2-like states. We further review the regulatory mechanisms of the IL-33-ILC2 axis in bronchopulmonary dysplasia, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and viral respiratory infections are also discussed, highlighting the remarkable functional plasticity of ILC2s. Targeting the IL-33-ILC2 axis and modulating ILC2 function represent therapeutic strategies for various type 2-mediated airway diseases.