NKG2D Mediates NK Cell Hyperresponsiveness and Influenza-Induced Pathologies in a Mouse Model of Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by peribronchial and perivascular inflammation and largely irreversible airflow obstruction. Acute disease exacerbations, due frequently to viral infections, lead to enhanced disease symptoms and contribute to long-term progression of COPD pathology. Previously, we demonstrated that NK cells from cigarette smoke (CS)-exposed mice exhibit enhanced effector functions in response to stimulating cytokines or toll-like receptor ligands. Here, we show that the activating receptor NKG2D is a key mediator for CS stimulated NK cell hyperresponsiveness as CS-exposed NKG2D-deficient mice (Klrk1-/-) did not exhibit enhanced effector functions as assessed by cytokine responsiveness. NK cell cytotoxicity against MHC class I-deficient targets was not affected in a COPD model. However, NK cells from CS-exposed mice exhibit greater cytotoxic activity towards cells that express the NKG2D ligand RAET1ε. We also demonstrate that NKG2D-deficent mice exhibit diminished airway damage and reduced inflammation in a model of viral COPD exacerbation without affecting viral clearance. Furthermore, adoptive transfer of NKG2D+ NK cells into CS-exposed, influenza-infected NKG2D-deficient mice recapitulated the phenotypes observed in CS-exposed, influenza-infected WT mice. Our findings indicate that NKG2D stimulation during long term CS-exposure is a central pathway in the development of NK cell hyperresponsiveness and influenza-mediated exacerbations of COPD.

Vanadium pentoxide increased PTEN and decreased SHP1 expression in NK-92MI cells, affecting PI3K-AKT-mTOR and Ras-MAPK pathways

“…Mice and humans exposed to pollutants derived from burning coal or diesel exhaust particles show a diminished NK cell function (Hurd and Whalen 2011;Dutta et al 2012;Wortham et al 2012;Muller et al 2013). Interleukin (IL)-2, a cytokine required for NK cell proliferation and activation (Suzuki et al 1983;Bi et al 2014;Leon et al 2014) has its effects mediated through IL-2 receptors and subsequently janus kinase/signal transducers and activators of transcription (JAK/STAT), phosphoinositide 3-kinase-protein kinase B-mechanistic target of Rapamycin (PI3K-Akt-mTOR) and mitogen-activated protein kinase (MAPK) signaling pathways (Lu et al 1998;Liao et al 2013).…”

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).…”