title: Elf3 regulates allergic airway inflammation by controlling dendritic cell-driven T cell differentiation.
abstract: Elf3 belongs to the Ets family of transcription factors and has been implicated in inflammation. Elf3 is highly expressed in the lungs, and Elf3(-/-) mice are impaired in IL-6 production after intranasal LPS exposure. To identify the role of Elf3 in Th17-driven pulmonary inflammation, we have performed epicutaneous sensitization of Elf3(-/-) mice with OVA followed by airway OVA challenge and have identified Elf3(-/-) mice to be impaired in induction of Th17 response, attributable to impairment of IL-6 production by dendritic cells (DCs). However, increased serum levels of OVA-specific IgG1 and IgE were observed, pointing toward an exaggerated Th2 response. To study Th2 response, we performed i.p. sensitization of Elf3(-/-) mice with OVA and confirmed loss of Elf3 to result in an aggravated Th2 response, characterized by increased generation of IL-4-producing T cells, increased levels of OVA-specific IgE and IgG1 Ab titers, and increased serum levels of Th2 cytokines, together with extensive inflammation and mucus production in airways. Elf3(-/-) DCs were impaired in priming Th1 differentiation, which, in turn, promoted Th2 differentiation. This was mediated by the ability of Elf3(-/-) DCs to undergo hypermaturation but secrete significantly lower levels of IL-12 in response to inflammatory stimuli. The impairment of IL-12 production was due to impairment of IL-12p40 gene induction in Elf3(-/-) DCs in response to inflammatory stimuli. Taken together, our study identifies a novel function of Elf3 in regulating allergic airway inflammation by regulating DC-driven Th1, Th2, and Th17 differentiation.
authors.affiliation: Physiology and Experimental Medicine Research Program, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kushwah
authors.forename: Jordan R
authors.initials: JR
authors.lastname: Oliver
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Chang
authors.forename: Jim
authors.initials: J
authors.lastname: Hu
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C494436:Elf3 protein, mouse; D014157:Transcription Factors; D018664:Interleukin-12; D010047:Ovalbumin