title: Cigarette smoke induction of osteopontin (SPP1) mediates T(H)17 inflammation in human and experimental emphysema.
abstract: Smoking-related lung diseases are among the leading causes of death worldwide, underscoring the need to understand their pathogenesis and develop new effective therapies. We have shown that CD1a+ antigen-presenting cells (APCs) from lungs of patients with emphysema can induce autoreactive T helper 1 (T(H)1) and T(H)17 cells. Similarly, the canonical cytokines interferon-γ (IFN-γ) and interleukin-17A (IL-17A) are specifically linked to lung destruction in smokers, but how smoke activates APCs to mediate emphysema remains unknown. Here, we show that, in addition to increasing IFN-γ expression, cigarette smoke increased the expression of IL-17A in both CD4+ and γδ T cells from mouse lung. IL-17A deficiency resulted in attenuation of, whereas lack of γδ T cells exacerbated, smoke-induced emphysema in mice. Adoptive transfer of lung APCs isolated from mice with emphysema revealed that this cell population was capable of transferring disease even in the absence of active smoke exposure, a process that was dependent on IL-17A expression. Spp1 (the gene for osteopontin) was highly expressed in the pathogenic lung APCs of smoke-exposed mice and was required for the T(H)17 responses and emphysema in vivo, in part through its inhibition of the expression of the transcription factor Irf7. Thus, the Spp1-Irf7 axis is critical for induction of pathological T(H)17 responses, revealing a major mechanism by which smoke activates lung APCs to induce emphysema and identifying a pathway that could be targeted for therapeutic purposes.
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Shan
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Yuan
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Song
authors.forename: Luz
authors.initials: L
authors.lastname: Roberts
authors.forename: Nazanin
authors.initials: N
authors.lastname: Zarinkamar
authors.forename: Alexander
authors.initials: A
authors.lastname: Seryshev
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Susan
authors.initials: S
authors.lastname: Hilsenbeck
authors.forename: Seon-Hee
authors.initials: SH
authors.lastname: Chang
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.forename: David B
authors.initials: DB
authors.lastname: Corry
authors.forename: Farrah
authors.initials: F
authors.lastname: Kheradmand
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology; D018949:Antigens, CD1 / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004646:Emphysema / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis*; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053495:Osteopontin / Q000096:biosynthesis*; D012907:Smoking / Q000009:adverse effects*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D018949:Antigens, CD1; C419393:CD1a antigen; D016207:Cytokines; D020381:Interleukin-17; C506895:SPP1 protein, human; C506896:Spp1 protein, mouse; D053495:Osteopontin; D007371:Interferon-gamma