Transcriptional and Epigenetic Modulation of Human Rhinovirus–Induced CXCL10 Production by Cigarette Smoke

Abstract

Human rhinovirus (HRV) triggers exacerbations of asthma and chronic obstructive pulmonary disease. Cigarette smoking is the primary risk factor for the development of chronic obstructive pulmonary disease, and 25% of individuals with asthma smoke. Smokers experience both longer and more severe colds. We previously showed that cigarette smoke extract (CSE) inhibited HRV-induced expression of a range of epithelial antiviral molecules. Here, we use CXCL10 as a model antiviral gene to examine the mechanisms by which CSE inhibits epithelial antiviral immunity. HRV-induced CXCL10 transcription depends on activation of NF-ĸB and IFN-regulatory factor-1 (IRF-1), and we now also implicate two signal transducer and activator of transcription (STAT) consensus sequences in the CXCL10 promoter in HRV-induced CXCL10 expression. CSE inhibited HRV-induced activation and nuclear translocation/binding of both NF-ĸB, and IRF-1 to their respective recognition sequences in the CXCL10 promoter. HRV also induced formation of complexes at the STAT region in the CXCL10 promoter, and HRV-induced activation of STAT-1 was inhibited by CSE. In addition, CSE inhibited HRV-induced chromatin accessibility around the transcriptional start site of the CXCL10 promoter. Although CSE inhibited HRV-induced expression of both the viral double-stranded RNA sensors, retinoic acid-inducible gene-I and melanoma differentiation-associated gene (MDA) 5, only specific short interfering RNA (siRNA) to MDA5, but not nontargeting siRNA, or siRNA to retinoic acid-inducible gene-I, inhibited HRV-induced CXCL10 induction. We conclude that CSE reduces chromatin accessibility and inhibits viral signaling via NF-ĸB, IRF-1, STAT-1, and MDA5. Thus, we show that CSE can simultaneously modulate multiple pathways linked to innate immune responses to HRV infection.

Transcriptomic and barrier responses of human airway epithelial cells exposed to cannabis smoke

“…To address the above issues, we performed a series of in vitro functional and transcriptomic experiments with a human airway epithelial cell line (Calu‐3) exposed to cannabis smoke, with tobacco smoke used as a positive control. To model cannabis smoke exposure, we used smoke conditioned media methods that have been validated for tobacco combustion experiments (Wirtz and Schmidt, ; Bernhard et al, ; Bauer et al, ; Hudy et al, ; Hudy and Proud, ; Hudy et al, ; Amatngalim et al, ; Jamieson et al, ). Comparison of differential gene expression patterns from our tobacco smoke conditioned media experiments in Calu‐3 cells to bronchial brushings from human tobacco smokers (Harvey et al, ; Tilley et al, ) and air‐liquid interface cultures of primary epithelial cells exposed to mainstream tobacco smoke (Mathis et al, ; Haswell et al, ; Haswell et al, ) revealed overlap, validating the relevance of our model.…”

Presence of rhinovirus in the respiratory tract of adolescents and young adults with asthma without symptoms of infection

“…Accordingly, there was a trend towards higher prevalence of smokers in HRV þ asthmatics versus HRV À asthmatics in our study. Cigarette smoke has been shown to down-regulate bronchial epithelial release of antiviral proteins, for example CXCL10, in response to rhinovirus infection [25,26], via the inhibition of multiple transcriptional pathways linked to innate immune responses [27]. Wos and colleagues have previously demonstrated that HRV can be detected in the lower respiratory tract of asthmatic patients more frequently than in healthy controls, in the absence of recent asthma exacerbations or signs of common cold [7].…”

Opposing Effects of Smoking in Ulcerative Colitis and Crohnʼs Disease May Be Explained by Differential Effects on Dendritic Cells

“…Elevation of CCL3 is reported in the rectal biopsies of patients with IBD. 23 Since rhinovirus infection activates pDC through TLR7 and 8 pathways, 11 CSE may disrupt a signaling pathway of TLR7 and 8, contributing to the decrease in elevated CXCL10 after CSE exposure in UC samples. 12 We observed that the decreased CCL3 from DC derived from patients with UC was associated with increased Foxp3+ T cells from patients with UC after CSE exposure, suggesting that an effect of CSE on DC from patients with UC was to increase DC ability to generate Foxp3+ T cells.…”