It takes two to tango: cigarette smoke partners with viruses to promote emphysema

Abstract

Viruses constitute a constant and renewed threat to humans. Not only do viruses cause disease directly due to their tissue tropism and pathogenicity, but they have also been linked to autoimmunity. In their study in this issue of the JCI, Kang et al. show that exposure to cigarette smoke induces alterations in the innate immune response to viral infection and that these changes hasten alveolar destruction characteristic of emphysema in mice (see the related beginning on page 2771). This study builds on evidence that patients with chronic obstructive pulmonary disease have clinical exacerbations associated with viral or bacterial infections, which lead to worsened lung function and increased mortality. This novel paradigm may aid related genetic, biomarker, and therapeutic developments and provides important insights into the pathogenesis of emphysematous lung destruction.

Figure 1. Synergistic interaction between cigarette smoke and RNA viruses in emphysema in mice.

The combination of exposure to cigarette smoke and RNA viruses leads to alveolar cell apoptosis involving type I epithelial, type II epithelial, and endothelial cells, and enhanced alveolar inflammation (with influx of neutrophils and macrophages). As shown by Kang et al. (5) in their study in this issue of the JCI, the process of alveolar destruction is set up via activation of the RLH adaptor protein MAVS, the cytokines IL-12, IL-18, and IFN-γ, and the phosphorylation of the kinase PKR (5). Furthermore, this process may course with an imbalance between matrix protease and antiproteases, favoring fragmentation of extracellular matrix proteins, including elastin. The cell signaling pathways triggered in alveolar epithelial cells infected by RNA viruses or synthetic dsRNA are represented in Figure 2.

Figure 2. Type I IFN production and PKR activation triggered by TLR3 or the RLH system by natural or synthetic dsRNA.

Activation of TLR3 by viral dsRNA leads to the recruitment of Toll/IL-1R homology domain–containing adaptor-inducing IFN-γ (TRIF), which activates TNF receptor–associated factor 6 (TRAF6), TANK-binding kinase 1/IκB kinase i (TBK1/IKKi), and receptor-interacting protein 1 (RIP1). TBK1 phosphorylates the IFN regulatory factors (IRFs) 3 and 7. Cytoplasmic dsRNA is also recognized by the RLH system, which interacts with MAVS via caspase recruitment domains (CARDs). MAVS recruits IKK and TBK1, and this converges with TLR3 signaling and leads to NF-κB activation and the induction of type I IFNs (e.g., INF-α and INF-β). MAVS also activates NF-κB through Fas-associated death domain–containing protein (FADD) and RIP1 interaction. The binding of type I IFNs to their receptor (IFNR) causes JAK/STAT-mediated synthesis of IFN-stimulated gene (ISG) products, including PKR. Although it is unclear whether PKR may be directly stimulated by the interaction of MAVS and dsRNA (as indicated by the dashed arrow), the endogenous protein PACT/RAX can also activate PKR independently of dsRNA. As suggested by the results of the current study by Kang et al. (5), cigarette smoke may (as reflected by dashed arrows) affect lung cell responses to RNA viruses by enhancing MAVS-PKR signaling and therefore trigger alveolar cell death. Figure modified with permission from Nature Immunology (9) and Cell Research (12).