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 (TH1) and TH17 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 TH17 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 TH17 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.

Immune Effects and Polychlorinated Biphenyls, Smoking and Alcohol

“…Therefore, since the distribution of TCR can vary according to age and genetic factors, the correlation between PCB and TCR found in our exposed workers seems to indicate a stimulation of the specific expression of TCR a-~involved in lymphocyte antigen recognition (23). On the contrary, the results of the study seem to exclude a direct effect of smoke and alcohol on TCR a-~and y-8 cells , in contrast with findings of some authors reporting an effect of smoke on TCR y-8 cells in humans and in mice (23,24). More intriguing and original, in PCB exposed subjects, is the relative % reduction of TCR y-8 T cells, in human particularly present in epithelia, both in the peripheral blood on the number of cigarettes smoked per day confirms the immunomodulating action of tobacco smoking that has already been reported by other authors, who found a greater and significant increase of Treg in bronchial alveolar lavage (BAL) of healthy smokers as compared to non-smokers/ex-smokers/smokers with chronic obstructive pulmonary disease (COPD) (9,10,30).…”

Helper T-Cell Type 17 Cytokines and Immunity in the Lung

“…However, IL-17 has been associated with certain forms of severe asthma (34), CF (40), and chronic obstructive pulmonary disease (44), and in these chronic lung diseases IL-17 may contribute to pathology. The role of IL-22 and IL-22-binding protein in these diseases needs to be defined.…”

Sulforaphane Protects from T Cell–Mediated Autoimmune Disease by Inhibition of IL-23 and IL-12 in Dendritic Cells

“…More recent reports unraveled beneficial effects of SFN in experimental chronic obstructive pulmonary disease (COPD) (28,53). SFN reduced pulmonary inflammation in COPD, a condition associated with Th17 responses (54,55). The aim of our study was to elucidate the immunoregulatory capabilities of SFN in terms of affected immune cells and underlying molecular mechanisms during T cell-mediated autoimmune responses.…”