Regulation of Retinoic Acid Receptor Beta by Interleukin-15 in the Lung during Cigarette Smoking and Influenza Virus Infection

Abstract

Virus-induced exacerbations often lead to further impairment of lung function in chronic obstructive pulmonary disease. IL-15 is critical in antiviral immune responses. Retinoic acid (RA) signaling plays an important role in tissue maintenance and repair, particularly in the lung. We studied RA signaling and its relation to IL-15 in the lung during cigarette smoke (CS) exposure and influenza virus infection. In vivo studies show that RA signaling is diminished by long-term CS exposure or influenza virus infection alone, which is further attenuated during infection after CS exposure. RA receptor b (RARb) is specifically decreased in the lung of IL-15 transgenic (overexpression; IL-15Tg) mice, and a greater reduction in RARb is found in these mice compared with wild-type (WT) mice after infection. RARb is increased in IL-15 knockout (IL-15KO) mice compared with WT mice after infection, and the additive effect of CS and virus on RARb down-regulation is diminished in IL-15KO mice. IL-15 receptor a (IL-15Ra) is increased and RARb is significantly decreased in lung interstitial macrophages from IL-15Tg mice compared with WT mice. In vitro studies show that IL-15 downregulates RARb in macrophages via IL-15Ra signaling during influenza virus infection. These studies suggest that RA signaling is significantly diminished in the lung by CS exposure and influenza virus infection. IL-15 specifically down-regulates RARb expression, and RARb may play a protective role in lung injury caused by CS exposure and viral infections.

BRD4 is involved in viral exacerbation of chronic obstructive pulmonary disease

“…In the present study, we show that inflammatory cytokines including IL-6 and IL-8 expression levels are increased significantly in the blood and sputum from COPD patients with viral exacerbation compared with stable patients. Using mouse models, our previous studies have shown that viral infection after CS exposure induces exaggerated lung inflammation [ 10 , 11 ], suggesting that CS and viruses might activate common pathways that lead to synergistic changes in certain mediators and subsequently an enhanced inflammatory response. In the present study, we mainly explored the roles of BRD4 in this exaggerated inflammation.…”

“…Our previous studies have explored the effects of viral infection after CS exposure on the lung in mouse models, suggesting that CS and viruses interact in a manner to induce exaggerated lung inflammation [ 10 , 11 ]. However the molecular mechanisms are complex, it has not been fully addressed whether these two challenges (CS and viruses) activate common pathways that can lead to synergistic changes in certain mediators and subsequently an enhanced inflammatory response in the lung.…”

In Vivo and In Vitro Studies of Cigarette Smoke Effects on Innate Responses to Influenza Virus: A Matter of Models?

“…However, animal experiments show that CS has both proinflammatory and immunosuppressive effects, depending on smoking length, smoking dose, virus dose, IAV strain, and sample collection time (Table 1). As an example, the length of CS exposure in mouse models may be as short as 3 days or as long as 6 months prior to IAV infection [72,73]. Notes: h = hour(s); d = day(s); wk = week.…”

Lung microvascular occlusion by platelet-rich neutrophil-platelet aggregates promotes cigarette smoke–induced severe flu

“…Here, we used a unique 2-hit model of CS exposure followed by a mild-dose of intranasal IAV infection in mice (20,21,23,24) that led to more severe lung injury than IAV infection alone. Using quantitative fluorescence intravital lung microscopy (qFILM) in live mice (25)(26)(27)(28)(29), we reveal for the first time to our knowledge that the prior exposure to CS exacerbates flu-induced lung injury by promoting lung microvascular occlusion by large platelet-rich neutrophil-platelet aggregates (NPAs), leading to the development of pulmonary ischemia followed by vascular leakage.…”