Cigarette smoke induction of osteopontin (SPP1) mediates T H17 inflammation in human and experimental emphysema

Ming Shan, Xiaoyi Yuan, Li Zhen Song, Luz Roberts, Nazanin Zarinkamar, Alexander Seryshev, Yiqun Zhang, Susan Hilsenbeck, Seon Hee Chang, Chen Dong, David Corry, Farrah Kheradmand

Research output: Contribution to journalArticle

109 Scopus citations

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 H1) and T H17 cells. Similarly, the canonical cytokines interferon-g (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 H17 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 H17 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.

Original languageEnglish (US)
Article number117ra9
JournalScience translational medicine
Volume4
Issue number117
DOIs
StatePublished - Jan 18 2012

ASJC Scopus subject areas

  • Medicine(all)

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