Cigarette smoke selectively enhances viral PAMP– and virus-induced pulmonary innate immune and remodeling responses in mice

Abstract

Viral infections have more severe consequences in patients who have been exposed to cigarette smoke (CS) than in those not exposed to CS. For example, in chronic obstructive pulmonary disease (COPD), viruses cause more severe disease exacerbation, heightened inflammation, and accelerated loss of lung function compared with other causes of disease exacerbation. Symptomatology and mortality in influenza-infected smokers is also enhanced. To test the hypothesis that these outcomes are caused by CS-induced alterations in innate immunity, we defined the effects of CS on pathogen-associated molecular pattern-induced (PAMP-induced) pulmonary inflammation and remodeling in mice. CS was found to enhance parenchymal and airway inflammation and apoptosis induced by the viral PAMP poly(I:C). CS and poly(I:C) also induced accelerated emphysema and airway fibrosis. The effects of a combination of CS and poly(I:C) were associated with early induction of type I IFN and IL-18, later induction of IL-12/IL-23 p40 and IFN-γ, and the activation of double-stranded RNAdependent protein kinase (PKR) and eukaryotic initiation factor-2α (eIF2α). Further analysis using mice lacking specific proteins indicated a role for TLR3-dependent and -independent pathways as well as a pathway or pathways that are dependent on mitochondrial antiviral signaling protein (MAVS), IL-18Rα, IFN-γ, and PKR. Importantly, CS enhanced the effects of influenza but not other agonists of innate immunity in a similar fashion. These studies demonstrate that CS selectively augments the airway and alveolar inflammatory and remodeling responses induced in the murine lung by viral PAMPs and viruses.

Chronic Cigarette Smoke Exposure Primes NK Cell Activation in a Mouse Model of Chronic Obstructive Pulmonary Disease

“…In contrast to the data presented in this study and the observations of others (16,35,36), there is some data suggesting that NK cells may be functionally suppressed in COPD. However, the interpretation of these reports is limited by small samples sizes, the use of non-COPD smokers with unknown patient characteristics, or in vitro treatment of PBMCs with Cs extract (55,56).…”

“…Priming of NK cell cytotoxicity is potentially a new mechanism for cellular apoptosis in COPD. Further, NK cell-mediated cellular apoptosis may be responsible for the observation of increased lung tissue destruction in CS-exposed mice postinfection (16).…”

“…The connection between viruses and COPD exacerbations remained mostly associative until, in a recent landmark study, Kang et al (16) experimentally demonstrated that exacerbations of symptoms following cigarette smoke (CS) exposure can be caused by viral infection. Key to the progression of COPD, viral infection following CS exposure led to enhanced pulmonary inflammation, increased alveolar apoptosis, accelerated emphysema, and airway fibrosis (16). However, the underlying cellular mechanisms responsible for these effects remain undiscovered.…”

Innate Immunity of Airway Epithelium and COPD

“…Inhibition of antiviral responses, in particular IFN and CXCL-10 responses appear to be due to acute exposure to cigarette smoke that occurs in vitro, because the airway epithelial cells obtained from COPD patients showed antiviral responses to rhinovirus infection which was in fact significantly higher than the cells obtained from nonsmokers (Schneider et al, 2010). Similar to our observations, mice exposed to cigarette smoke and poly I:C or influenza virus showed increased IFN responses and this was attributed to pathogenesis of COPD (Kang et al, 2008).…”

The Natural Cytotoxicity Receptor NKp46 Is Dispensable for IL-22-Mediated Innate Intestinal Immune Defense against Citrobacter rodentium

“…Lastly, by comparing C. rodentium infection in T and B celldeficient mice that were competent or incompetent for NKp46 triggering (Rag2 (38). The critical role of IL-12 and/or IL-23 in vivo for immunity to C. rodentium was reported by MacDonald and colleagues (39), who found increased mortality and compromised C. rodentium control in mice lacking the IL-12p40 subunit of IL-12 and IL-23.…”