Cigarette Smoke Induction of Osteopontin (SPP1) Mediates TH17 Inflammation in Human and Experimental Emphysema

The destruction of lung tissue in emphysema is orchestrated by antigen-presenting cells that have been activated by smoke. When Smoke Gets in Your Lungs Even without the warning label on the cigarette box, everyone knows that tobacco smoke is bad for you. But what really happens inside the lung to cause disease? Shan et al. have married studies in patients with emphysema and in mice exposed to tobacco smoke for several months to identify some of the crucial events that cause one serious lung disease—emphysema. They find that the antigen-presenting cells of the immune system are culpable; indeed, transfer of these cells from a mouse with emphysema into a healthy mouse induces disease. Further, they identify the signaling molecules in these cells that are activated by smoke (osteopontin and the transcription factor Irf7), which may prove to be useful targets for therapies. First, the authors verified that mice exposed to smoke carried similar immune cells in their lungs as do human smokers. These cells, including their secretory products IFN-γ and IL-17A, trigger the lung tissue destruction that robs emphysema patients of their ability to breathe. What activates these immune responses? The authors finger antigen-presenting cells by transferring these cells from diseased mice to healthy ones, showing that the disease transfers along with them. Then, tracing the process one step back, the authors look for smoke-induced genes in these antigen-presenting cells and identify osteopontin and Irf7, a transcription factor regulated by Spp1, as key mediators of smoke-induced cell activation. There are earlier steps in the process that have yet to be elucidated, but the cause of the havoc wreaked inside the lung by tobacco smoke is getting clearer. As a bonus, another cell type that participates in the mayhem unleashed in the emphysemic lung was uncovered. The γδ T cell, usually very rare, was unexpectedly found to be a good guy. Induced along with the destructive cells, these cells curtailed the damage but ultimately lost the battle. Perhaps bolstering the abilities of the helpful γδ T cells could ultimately help to treat serious immunogenic destructive processes in the lung. 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.