Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology

Current therapies for asthma focus on reducing the frequency and severity of exacerbations by attenuating bronchiole inflammation and airway hyperreactivity. The limited efficacy of treatments, such as inhaled corticosteroids, to reduce the inflammatory response in some chronic asthmatics illustrates the need for further research into mechanisms underlying the pathophysiology of asthma1–3. Three epithelial-derived type 2 inflammation associated cytokines, IL-25, thymic stromal lymphopoietin (TSLP) and IL-33, may represent targets for therapeutic treatment in severe asthma. IL-25, in particular, has been reported to enhance responses and further exacerbate allergic disease. In an original study4, the systemic injection of IL-25 into Rag−/− mice induced type 2 cytokine expression and eosinophilia, demonstrating that T cell–independent mechanisms could drive type 2 inflammation. The IL-17 family member IL-25 (IL-17E) regulates multiple aspects of mucosal immunity by promoting type 2 inflammation via production of IL-4, IL-5, and IL-13 (refs. 4–6). Pulmonary IL-25 is produced by eosinophils7,8, mast cells and airway epithelial cells and stimulates asthma-like, allergic inflammation characterized by airway hyperreactivity, mucus production, airway eosinophilia and increased serum IgE9. The induction of these responses requires binding of a noncovalently bound IL-25 homodimer to the IL-17RA–IL-17RB heterodimer10, of which IL-17RB represents an IL-25–specific moiety in the lung11. IL-25 is known to enhance T helper type 2 effector functions via Act1-dependent and TRAF6-dependent nuclear factor-κB activation12–15. Multiple cell types in the lung, including memory16 and effector14,16 T cells, invariant natural killer T cells17, antigenpresenting cells and airway smooth muscle cells, have been shown to express IL-17RB, whereas eosinophils do not7. Several studies have also identified additional IL-25–responsive, type 2 cytokine– producing non-B, non-T (NBNT) cell populations5,18–20, and a recent investigation reported increased expression of IL-25 and its receptor in the airways of individuals with asthma after allergen provocation21. This work reports that repeated allergen exposure upregulates both pulmonary IL-25 and IL-17RB in a mouse model of persistent allergic airway disease and induces the accumulation of a previously undescribed IL-4– and IL-13–producing IL-17RB+ T2M population in the lung. Cytokine production in T2M cells is promoted by IL-25, and these cells are both pathogenic and steroid resistant. Moreover, IL-4– and IL-13–producing T2M-like cells are present in the peripheral blood of human subjects with asthma.