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

Abstract

Chronic obstructive pulmonary disease (COPD) is a debilitating, progressive lung disease punctuated by exacerbations of symptoms. COPD exacerbations are most often associated with viral infections, and exposure to cigarette smoke (CS) followed by viral infection has been shown experimentally to enhance lung inflammation, tissue destruction, and airway fibrosis. Despite this, however, the cellular mechanisms responsible for this effect are unknown. In this study, we examined NK cell function in a mouse model of COPD given the vital role of NK cells following viral infection. Ex vivo stimulation of lung leukocytes with poly(I:C), ssRNA40, or ODN1826 enhanced production of NK cell-derived IFN-γ in CS-exposed mice. NK cells from CS-exposed mice exhibited a novel form of priming; highly purified NK cells from CS-exposed mice, relative to NK cells from filtered air-exposed mice, produced more IFN-γ following stimulation with IL-12, IL-18, or both. Further, NK cell priming was lost following smoking cessation. NKG2D stimulation through overexpression of Raet1 on the lung epithelium primed NK cell responsiveness to poly(I:C), ssRNA40, or ODN1826 stimulation, but not cytokine stimulation. In addition, NK cells from CS-exposed mice expressed more cell surface CD107a upon stimulation, demonstrating that the NK cell degranulation response was also primed. Together, these results reveal a novel mechanism of activation of the innate immune system and highlight NK cells as important cellular targets in controlling COPD exacerbations.

Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the human lung

“…Although we found that CSE attenuates the influenza-induced innate antiviral response in our human model, as other observations from human cells (25)(26), there are some data suggesting that CS exposure selectively enhances viral-induced pulmonary innate responses in mice (16,27). Influenza virus is not a natural pathogen of mice and requires several passages through them to become mouse adapted and cause disease.…”

Regulation of Retinoic Acid Receptor Beta by Interleukin-15 in the Lung during Cigarette Smoking and Influenza Virus Infection

“…These clinical findings suggest that the interactions between CS exposure and viral infections play important roles in clinical scenarios that include virus-induced COPD exacerbations, which have become important clinical parameters in understanding the pathogenesis of COPD. Studies from our laboratory and others have demonstrated that CS and viruses interact in a manner to induce exaggerated inflammatory, emphysema-like, and airway fibrotic changes in animal CS exposure and infection models (11)(12)(13)(14)(15). Studying the mechanisms of how CS exposure and viral infections interact in the lung and affect these pulmonary tissue changes will provide potentially important therapeutic target for diseases such as COPD.…”

“…These studies demonstrated that CS and viruses interact in a manner to induce exaggerated pulmonary inflammation and accelerated emphysema and airway fibrosis (11). However, although almost all of these studies focused on the innate immune mechanisms (11)(12)(13)(14), the possibility that other signaling pathways could also contribute to these effects has not been fully addressed. IL-15 is a proinflammatory cytokine that is expressed by epithelial cells and antigen-presenting cells (APCs), including macrophages and dendritic cells.…”

“…Given the importance of virus-induced exacerbations in COPD and that CS can enhance the inflammatory and remodeling effects of influenza virus (11)(12)(13)(14)(15), C57BL/6 mice were exposed to NS or CS for 1 month and then infected with influenza virus or vehicle control. On Day 7 after infection, total leukocyte counts in bronchoalveolar lavage fluid (BALF) and IL-15 protein levels by ELISA in lung tissue were determined.…”

“…Previous studies from our laboratory and others have explored the effects of viral infections after CS exposure on the lung in mouse models (11)(12)(13)(14)(15). These studies demonstrated that CS and viruses interact in a manner to induce exaggerated pulmonary inflammation and accelerated emphysema and airway fibrosis (11).…”