Azithromycin augments rhinovirus-induced IFNβ via cytosolic MDA5 in experimental models of asthma exacerbation
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Mandy Menzel1, Hamid Akbarshahi1, Ellen Tufvesson2, Carl Persson3, Leif Bjermer2, Lena Uller1
1Respiratory Immunopharmacology, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
2Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, 22184 Lund, Sweden
3Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, 22184 Lund, Sweden
Lena Uller, email: Lena.Uller@med.lu.se
Keywords: asthma, rhinovirus, azithromycin, MDA5, IFNβ
Received: February 08, 2017 Accepted: March 12, 2017 Published: March 18, 2017
Deficient production of anti-viral interferons (IFNs) may be involved in causing viral-induced asthma exacerbations. Hence, drugs inducing lung IFN production would be warranted. Azithromycin may reduce asthma exacerbations but its modus operandi is unknown. Here, we investigated if azithromycin induces IFNβ expression in vitro in rhinovirus-infected bronchial epithelial cells from asthmatic donors and in vivo in our allergic inflammation-based mouse model of viral stimulus-induced asthma exacerbations. Azithromycin dose-dependently augmented viral-induced IFNβ expression in asthmatic, but not in healthy bronchial epithelial cells. The effect negatively correlated with viral load. Knockdown of MDA5 and RIG-I by siRNA showed involvement of MDA5 but not RIG-I in azithromycin’s IFN-inducing effects in vitro. In vivo azithromycin induced IFNβ protein, restoring a reduced lung IFN response exclusively in allergic exacerbating mice. This was associated with induction of interferon-stimulated genes and MDA5, but not RIG-I. We suggest that clinically relevant concentrations of azithromycin produce MDA5-dependent, anti-viral, IFN-inducing effects in bronchial epithelium distinctly from asthmatic donors. Similarly, azithromycin induced MDA5-associated IFN in virally stimulated lungs in vivo exclusively in allergic mice. Effects of azithromycin and MDA5-active drugs on viral-induced exacerbations deserve further research.
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