Innate imprinting of resident alveolar macrophages in RSV-induced allergic asthma exacerbations (P6003)

Abstract

Abstract Acute RSV-infections are seen as instigators of exacerbations in allergic asthma patients. The question which cells and/or molecules that orchestrate viral-induced asthma exacerbations remains unanswered. We now show that the innate (antiviral) functionality of post-asthma resident alveolar macrophages (rAM), present after the clearance of the allergic bronchial inflammation, is imprinted by this preceding allergic inflammation. In contrast to naïve rAM, post-asthma rAM exhibited strong proinflammatory reactivity during RSV-infection which significantly contributed to the increased global pulmonary inflammation observed in RSV-infected post-asthma mice. The strong proinflammatory reactivity of post-asthma rAM was mainly due to increased NF-κB p65 activation in these cells upon RSV-infection. Furthermore, compared to naïve rAM, post-asthma rAM displayed no direct contribution to virus clearance. In fact, post-asthma rAM did not show efficient uptake of the virus. Finally, compared to naïve rAM, the basal activation state of post-asthma rAM was found to be strongly skewed towards an M2-phenotype. Consequently, the polarized M2-activation status of post-asthma rAM can serve as a possible explanation for the aberrant antiviral innate responses of these cells. Together, innate imprinting of rAM by a preceding allergic inflammation strongly impairs RSV-antiviral responses of the post-asthma lungs and can therefore contribute to the onset of asthma exacerbations.