Plasmacytoid dendritic cells drive acute asthma exacerbations

Background: Although acute exacerbations, mostly triggered by viruses, account for the majority of hospitalizations in asthma, there is still very little known about the pathophysiological mechanisms involved. Plasmacytoid DCs (pDCs), prominent cells of antiviral immunity, exhibit potent pro-inflammatory and tolerogenic functions depending on the context, yet their involvement in asthma exacerbations remains unexplored. Objectives: We sought to investigate the role of pDCs in allergic airway inflammation and acute exacerbations of asthma. Methods: Animal models of allergic airway disease (AAD) and virus-induced AAD exacerbations were employed to dissect pDC function in vivo and unwind potential mechanisms involved. Sputum from asthma patients with stable disease or acute exacerbations was further studied to determine pDC presence and explore disease-relevant associations. Results: pDCs are key mediators of the immuno-inflammatory cascade that drives asthma exacerbations. In animal models of AAD and RV-induced AAD exacerbations, pDCs are recruited to the lung during inflammation and migrate to the draining lymph nodes to boost Th2-mediated effector responses. Accordingly, pDC depletion post-allergen challenge or during RV infection abrogates exacerbation of inflammation and disease. Central to this process is IL-25, induced by allergen challenge or RV infection that conditions pDCs for proinflammatory function. Consistently, in asthma patients pDCs are markedly increased during exacerbations, and correlate with the severity of inflammation and the risk for asthmatic attacks. Conclusions: Our studies uncover a previously unsuspected role of pDCs in asthma exacerbations with important diagnostic, prognostic and therapeutic implications. They also propose the therapeutic targeting of pDCs for the treatment of acute asthma.