Cigarette Smoke Primes the Pulmonary Environment to IL-1α/CXCR-2–Dependent Nontypeable Haemophilus influenzae–Exacerbated Neutrophilia in Mice

Abstract

Cigarette smoke has a broad impact on the mucosal environment with the ability to alter host defense mechanisms. Within the context of a bacterial infection, this altered host response is often accompanied by exacerbated cellular inflammation, characterized by increased neutrophilia. The current study investigated the mechanisms of neutrophil recruitment in a murine model of cigarette smoke exposure and, subsequently, a model of both cigarette smoke exposure and bacterial infection. We investigated the role of IL-1 signaling in neutrophil recruitment and found that cigarette smoke-induced neutrophilia was dependent on IL-1α produced by alveolar macrophages. In addition to being the crucial source of IL-1α, alveolar macrophages isolated from smoke-exposed mice were primed for excessive IL-1α production in response to bacterial ligands. To test the relevance of exaggerated IL-1α production in neutrophil recruitment, a model of cigarette smoke exposure and nontypeable Haemophilus influenzae infection was developed. Mice exposed to cigarette smoke elaborated an exacerbated CXCR2-dependent neutrophilia in response to nontypeable Haemophilus influenzae. Exacerbated neutrophilia was dependent on IL-1α priming of the pulmonary environment by cigarette smoke as exaggerated neutrophilia was dependent on IL-1 signaling. These data characterize a novel mechanism of cigarette smoke priming the lung mucosa toward greater IL-1–driven neutrophilic responses to bacteria, with a central role for the alveolar macrophage in this process.

Cigarette Smoke Attenuates the Nasal Host Response to Streptococcus pneumoniae and Predisposes to Invasive Pneumococcal Disease in Mice

“…A similar effect of cigarette smoke was observed in humans, where nasal IL-6 expression was decreased in young healthy smokers following nasal inoculation with live attenuated influenza virus (56). In contrast, we have previously shown that alveolar macrophage responses to nontypeable Haemophilus influenzae (NTHi) in the lungs are skewed by cigarette smoke, suppressing the expression of some inflammatory mediators while augmenting that of others, including IL-1␣, which contributed to excessive lung neutrophilia in response to bacterial infection (57). This could be attributed to differential regulation of inflammatory processes by cigarette smoke in the upper and lower respiratory tracts, as suggested by Huvenne et al (58).…”

Increased Myeloid Cell Production and Lung Bacterial Clearance in Mice Exposed to Cigarette Smoke

“…In a recent study, Nikota et al. showed that cigarette smoke primed the lung environment, including IL-1α production by alveolar macrophages and subsequent increased neutrophil mobilization via the chemokine receptor CXCR2 (37). Upon repeated infections with NTHi, smoke-induced inflammation eventually led to increased lung compliance and structural damage.…”

Combined exposure to bacteria and cigarette smoke resembles characteristic phenotypes of human COPD in a murine disease model

“…In a 4 weeks study, concomitant exposure to CS and S. aureus enterotoxin B induced both goblet cell hyperplasia in the airway wall and the formation of dense, organized aggregates of B-and T-lymphocytes (Huvenne et al, 2011). In 8-week exposure models, the combined exposure to CS and NTHi resulted in airway remodeling, increased inflammation, emphysema (Ganesan et al, 2014) and IL-1 driven neutrophilic inflammation (Nikota et al, 2014). Chronic exposure to NTHi lysate caused infiltration with lymphocytes and collagen deposition, but no mucus cell hyperplasia (Moghaddam et al, 2008).…”