Interleukin-15 Regulates Retinoic Acid Receptor Beta in the Lung During Cigarette Smoking and Influenza Virus Infection

Jianmiao Wang , Wei Liu , Chad Marion , Rajvir Singh , Nathaniel Andrews , Chun Geun Lee , Jack A. Elias , and Charles S. Dela Cruz

Virus-induced exacerbations often lead to further impairment of lung function in chronic obstructive pulmonary disease. Interleukin (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 following CS exposure. RA receptor β (RARβ) is specifically decreased in the lung of IL-15 transgenic (overexpression; IL-15Tg) mice, and a greater reduction in RARβ is found in these mice compared with wild type (WT) after infection. RARβ is increased in IL-15 knockout (IL-15KO) mice compared with WT after infection and the additive effect of CS and virus on RARβ downregulation is diminished in IL-15KO mice. IL-15 receptor α (IL-15Rα) is increased and RARβ is significantly decreased in lung interstitial macrophages from IL-15Tg mice compared with WT. In vitro studies show that IL-15 downregulates RARβ in macrophages via IL-15Rα 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 downregulates RARβ expression and RARβ may play a protective role in lung injury caused by CS exposure and viral infections.