Abstract
Long-term exposure to cigarette smoke (CS) can have deleterious effects on lung epithelial cells including cell death and the initiation of inflammatory responses. CS-induced cell injury can elaborate cell surface signals and cellular byproducts that stimulate immune system surveillance. Our previous work has shown that the expression of ligands for the cytotoxic lymphocyte activating receptor NKG2D is enhanced in patients with COPD and that the induction of these ligands in a mouse model can replicate COPD pathologies. Here, we extend these findings to demonstrate a role for the NKG2D receptor in CS-induced pathophysiology and provide evidence linking nucleic acid-sensing endosomal toll-like receptor (TLR) signaling to COPD pathology through NKG2D activation. Specifically, we show that mice deficient in NKG2D exhibit attenuated pulmonary inflammation and airspace enlargement in a model of CS-induced emphysema. Additionally, we show that CS exposure induces the release of free nucleic acids in the bronchoalveolar lavage and that direct exposure of mouse lung epithelial cells to cigarette smoke extract similarly induces functional nucleic acids as assessed by TLR3, 7, and 9 reporter cell lines. We demonstrate that exposure of mouse lung epithelial cells to TLR ligands stimulates the surface expression of RAET1, a ligand for NKG2D, and that mice deficient in TLR3/7/9 receptor signaling do not exhibit CS-induced NK cell hyperresponsiveness and airspace enlargement. The findings indicate that CS-induced airway injury stimulates TLR signaling by endogenous nucleic acids leading to elevated NKG2D ligand expression. Activation of these pathways plays a major role in the altered NK cell function, pulmonary inflammation and remodeling related to long-term CS exposure.
Highlights
Long-term exposure to cigarette smoke (CS) leads to a progressive decline in pulmonary function and can result in the onset of diseases such as chronic obstructive pulmonary disease (COPD)
We examined the effects of long-term CS exposure in NKG2D–deficient mice to further investigate the role of NKG2D in the increased inflammation and development of alveolar destruction
Unc93b1 mutants (TLR3/7/9 signaling deficient) and WT C57BL/6 mice were exposed to CS or filtered air (FA) for 6 months. (A) Raet1expression was measured by RT-PCR from the lungs of exposed mice
Summary
Long-term exposure to cigarette smoke (CS) leads to a progressive decline in pulmonary function and can result in the onset of diseases such as chronic obstructive pulmonary disease (COPD). COPD is a complex disease characterized by alterations in airway epithelial cells, peribronchial and perivascular inflammation and permanent alveolar enlargement [1]. Cellular subsets of both the innate and adaptive immune response coordinate inflammation and tissue destruction contributing to the pathogenesis of COPD [2]. NKG2D (Klrk1) is distinguished as it is present on virtually all NK cells, targets stress- and infection-induced ligands, and can overcome inhibitory signals to mediate cytotoxicity and cytokine release [6]. In the context of CS exposure, NKG2D ligands are induced on stressed human airway epithelial cells [8], and persistently expressed on pulmonary epithelial cells of smokers with and without COPD [3]. RAET1 expression is induced in the alveolar and airway epithelium in a mouse model of COPD [3]
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