title: Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology.
abstract: Interleukin-25 (IL-25) is a cytokine associated with allergy and asthma that functions to promote type 2 immune responses at mucosal epithelial surfaces and serves to protect against helminth parasitic infections in the intestinal tract. This study identifies the IL-25 receptor, IL-17RB, as a key mediator of both innate and adaptive pulmonary type 2 immune responses. Allergen exposure upregulated IL-25 and induced type 2 cytokine production in a previously undescribed granulocytic population, termed type 2 myeloid (T2M) cells. Il17rb(-/-) mice showed reduced lung pathology after chronic allergen exposure and decreased type 2 cytokine production in T2M cells and CD4(+) T lymphocytes. Airway instillation of IL-25 induced IL-4 and IL-13 production in T2M cells, demonstrating their importance in eliciting T cell-independent inflammation. The adoptive transfer of T2M cells reconstituted IL-25-mediated responses in Il17rb(-/-) mice. High-dose dexamethasone treatment did not reduce the IL-25-induced T2M pulmonary response. Finally, a similar IL-4- and IL-13-producing granulocytic population was identified in peripheral blood of human subjects with asthma. These data establish IL-25 and its receptor IL-17RB as targets for innate and adaptive immune responses in chronic allergic airway disease and identify T2M cells as a new steroid-resistant cell population.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, USA.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Petersen
authors.forename: Alison L
authors.initials: AL
authors.lastname: Budelsky
authors.forename: Alan P
authors.initials: AP
authors.lastname: Baptist
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Schaller
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D007378:Interleukins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology*; D053722:Receptors, Interleukin-17 / Q000502:physiology*
chemical_list: D016207:Cytokines; C485810:Il17rb protein, mouse; D007378:Interleukins; C442281:Mydgf protein, mouse; D053722:Receptors, Interleukin-17; D003907:Dexamethasone