Rhinovirus-Induced Exacerbations of Asthma and COPD

Hershenson, Marc B.

To address this further, we isolated bronchoalveolar lavage macrophages from control and ovalbumin-sensitized and -challenged mice and infected them with rhinovirus ex vivo. Macrophages from control mice showed ample Th1 cytokine (TNF-, IL-12p70) expression in response to RV infection, but little or no Th2 cytokine (IL-4, IL-13, CCL11) production. In contrast, BAL cells from ovalbumin-sensitized and -challenged mice showed brisk Th2 responses to ex vivo infection, but decreased Th1 responses. This pattern of cytokine expression was consistent with a change in phenotype from M1 to alternatively activated M2 macrophages [99] . We confirmed this by measurement of M2 markers such as arginase-1, YM-1, and MGL-2. Furthermore, flow cytometry showed high levels of CD11b expression, indicative of exudative macrophages found after lung infection or injury. To determine the requirement of these macrophages for the observed airways hyperresponsiveness of rhinovirusinfected and ovalbumin-sensitized and -challenged mice, we depleted the macrophages using clodronate liposomes. Administration of clodronate decreased the number of airway macrophages, but not neutrophils or lymphocytes. However the lungs of mice receiving clodronate showed reduced levels of CCL11, eosinophils, IL-13, and airways responsiveness, demonstrating that macrophages are responsible for RV-induced airway responses in mice with preexisting allergic airways disease. The production of Th2 cytokines by lung macrophages is consistent with recent work showing that, in addition to Th2 helper T cells, innate immune cells may contribute to the production of Th2 cytokines in asthma [100] [101] [102] [103] [104] [105] [106] [107] . Finally, our unpublished experiments indicate that, under certain circumstances, M1-polarized macrophages may also be targeted by RV infection. Taken together, our data suggest that, rather than causing epithelial infection or damage, RV elicits asthma exacerbations by infecting inflammatory cells, in particular cells of the monocyte/macrophage lineage.