Amphiregulin-Producing Pathogenic Memory T Helper 2 Cells Instruct Eosinophils to Secrete Osteopontin and Facilitate Airway Fibrosis

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SummaryMemory T cells provide long-lasting protective immunity, and distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes remain unknown. We found that interleukin-33 (IL-33) enhanced amphiregulin production by the IL-33 receptor, ST2hi memory T helper 2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of amphiregulin-producing CRTH2hiCD161hiCD45RO+CD4+ Th2 cells and osteopontin-producing eosinophils. Thus, the IL-33-amphiregulin-osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders.Graphical AbstractHighlightsPathogenic memory Th2 cells induce amphiregulin (Areg) via IL-33Areg reprograms the transcriptome of eosinophils toward an inflammatory stateAreg-reprogramed eosinophils produce osteopontin to trigger airway fibrosisAreg+ Th2 cells and osteopontin+ eosinophils co-localize in fibrotic ECRS polypsAsthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. Morimoto and colleagues find that the IL-33-ST2-amphiregulin-EGRF-osteopontin axis directs fibrotic responses in chronic allergic inflammation with the involvement of airway epithelial cells, pathogenic memory Th2 cells, and inflammatory eosinophils in both mouse and human.

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