CCR5 Antagonist Maraviroc Inhibits Acute Exacerbation of Lung Inflammation Triggered by Influenza Virus in Cigarette Smoke-Exposed Mice

Abstract

Influenza A virus (IAV) infection is a common cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Since macrophage inflammatory protein 1 α, a chemokine that acts through CC-chemokine receptor (CCR)-5, appears elevated in COPD patients’ airways, we evaluated whether CCR5 antagonist Maraviroc could inhibit the exacerbated lung inflammatory response noted after IAV H1N1 infection in mice exposed to cigarette smoke (Cs). C57BL/6 mice, subjected or not to Cs inhalation for 11 days, were infected with H1N1 at day 7. Maraviroc (10 mg/kg) or dexamethasone (1 mg/kg) were given in a therapeutic schedule, followed by the analyses of lung function, survival rate, and inflammatory changes. As compared to mice subjected to Cs or H1N1 alone, the insult combination significantly worsened airway obstruction, neutrophil infiltration in the airways, and the survival rate. All changes were sensitive to Maraviroc but not dexamethasone. Maraviroc also reduced the accumulation of neutrophils and macrophages as well as CXCL1 production in the lung tissue, and serum levels of IL-6, whereas comparable viral titers in the lungs were noted in all infected groups. Collectively, these findings suggest that Maraviroc oral treatment could be an effective therapy for controlling acute exacerbations of respiratory diseases such as COPD.

Effects of Cigarette Smoking on Influenza Virus/Host Interplay

“…Once drawn into the lungs, they bombard the respiratory epithelial cells, triggering the release of pro-inflammatory cytokines (such as IL-8 and TNF-α) by resident immune cells and epithelial cells alike. This results in the elevated recruitment of neutrophils in acute cigarette smoke exposure and increased macrophage levels in the lungs [30][31][32][33]. Upon arrival, innate immune cells aid in the clearance of smoke particles, but also perpetuate inflammation and cellular recruitment by releasing pro-inflammatory cytokines and chemokines in the affected tissue.…”

The Dual Role of CCR5 in the Course of Influenza Infection: Exploring Treatment Opportunities

“…Therefore, CCR5 signaling can impact the antiviral responses mediated by both epithelial and immune cells and, this should be taken into consideration when developing therapeutic strategies targeting this receptor for other inflammatory diseases. Interestingly, a recent study provided strong evidence for the protective role of CCR5 antagonism during Chronic Obstructive Pulmonary Disease (COPD) exacerbations caused by influenza in which CCL3 levels but no CCL5, correlated with an exacerbated inflammatory process ( 46 ). Maraviroc treatment during COPD viral exacerbations protected mice from the lethal pulmonary inflammation without affecting viral replication ( 46 ).…”

“…Interestingly, a recent study provided strong evidence for the protective role of CCR5 antagonism during Chronic Obstructive Pulmonary Disease (COPD) exacerbations caused by influenza in which CCL3 levels but no CCL5, correlated with an exacerbated inflammatory process ( 46 ). Maraviroc treatment during COPD viral exacerbations protected mice from the lethal pulmonary inflammation without affecting viral replication ( 46 ). In this regard, understanding the response to the virus and distinguishing between harmful and protective inflammation is crucial.…”

“…As aforementioned, CCR5 contribution during influenza infection appears to be crucial for the development of an antiviral response and the proper induction of immunologic memory. On the other hand, CCR5 activation is associated with excessive recruitment of neutrophils, inflammatory monocytes and NK cells in models of severe influenza pneumonia ( 24 , 46 , 68 ). This dual role of a chemokine receptor in the context of lung diseases is not an exclusive characteristic of CCR5 ( 69 ).…”

“…This dual role of a chemokine receptor in the context of lung diseases is not an exclusive characteristic of CCR5 ( 69 ). Currently, the information obtained by the use of animal models suggests that while some CCR5 ligands, like CCL5, can play a protective role in influenza infection ( 23 , 33 ) others, like CCL3, may contribute to an overwhelming inflammatory process which can harm the lung tissue ( 46 , 70 ). Many pharmacological strategies that aim to impair CCR5 activity and endocytosis have been developed to fight HIV infection and were already tested in humans showing good safety profiles and effective antagonism properties.…”