IL-25 orchestrates activation of Thelper cells via conventional dendritic cells in tissue to exacerbate chronic HDM-induced asthma pathology

• Published in: The Journal of immunology (1950) Vol. 203; no. 8; pp. 2319 - 2327
• Main Authors: Claudio, Estefania, Wang, Hongshan, Kamenyeva, Olena, Tang, Wanhu, Ha, Hye-lin, Siebenlist, Ulrich
• Format: Journal Article
• Language: English
• Published: 11-09-2019
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1900254

House dust mites (HDM) extract is a common trigger of asthma in humans. Chronic exposure to HDM also induces asthma-like pathology in mice. Allergic responses to HDM and other allergens are linked to release of IL-25, IL-33 and TSLP by epithelial cells; these cytokines, especially IL-33, target innate lymphoid cells-2 (ILC2s) to produce type-2 cytokines. To what extent and by what mechanisms IL-25 contributes to chronic HDM-induced pathology is not well understood. In humans, elevated levels of IL-25 appear to be associated with cases of uncontrolled asthma and exacerbated attacks. Here we demonstrate that blockade of IL-25 signaling in either lung conventional dendritic cells (cDCs) or in T cells resulted in similar decreases in production of IL-13 and IL-9 by T cells, reduced mast cell accumulation and tissue remodeling, and improved lung function, but had only modest effects on eosinophilia. Stimulation of cDCs by IL-25 promoted proximal accumulation of T helper cells (Th) and stimulation of Th cells by IL-25 locally promoted IL-13 and IL-9 production. IL-25 made notable contributions to chronic HDM-induced allergic asthma pathology by facilitating clustering and cross-stimulation of different cell types in tissue. Therapeutic targeting of IL-25 in combination with other treatments may be beneficial.