Journal
IMMUNITY
Volume 49, Issue 1, Pages 134-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2018.04.023
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Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT Japan) [26221305, 17K08876, 18K07164, 18K16830]
- AMED-CREST, AMED [JP16gm0410009]
- AMEDPRIME, AMED [JP18gm6110005]
- Practical Research Project for Allergic Diseases and Immunology (Research on Allergic Diseases and Immunology) from AMED [JP18ek0410030, JP18ek0410045]
- Takeda Science Foundation
- Naito Foundation
- Grants-in-Aid for Scientific Research [17K08876, 18K07164, 18K16830] Funding Source: KAKEN
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Memory 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, ST2(hi) 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 CRTH2(hi) CD161(hi) CD45RO(+)CD4(+) Th2 cells and osteopontin-producing eosinophils. Thus, the IL-33-am-phiregulin-osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders.
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