Rhinovirus-infected COPD airway cells modulates innate immune function of alveolar macrophages via TGF-β1

Abstract

Abstract Airway epithelium, a primary target for rhinovirus (RV), modulates innate immune responses of other cell types including, pulmonary macrophages. The majority of RV-infected patients with chronic obstructive pulmonary disease (COPD) also acquire secondary bacterial infections. We hypothesized that COPD airway epithelial cells (AEC) affect pulmonary macrophage innate immune functions through secreted products, thus promoting secondary bacterial infections. Pulmonary macrophages were pretreated with spent medium of RV- or sham-infected normal and COPD AEC and examined for innate immune responses to non-typeable H. influenzae (NTHI). Macrophages pretreated with spent medium from RV-infected COPD, but not normal AEC showed a defect in bacterial phagocytosis, and in the expression of cathelicidin, an antimicrobial peptide, and enhanced expression of CCL-20, TNF-α and CXCL-10 in response to NTHi. Proteomic analysis identified the presence of TGF-β1, tenascin C, fibronectin-1 in the secretome of RV-infected COPD, but not normal AEC. Neutralization of TGF-β1 abolished the inhibitory effects of spent medium from RV-infected COPD AEC on NTHi-induced cathelicidin and restored phagocytosis without significantly affecting NTHi-stimulated CCL-20, TNF-α and CXCL-10 in macrophages. These results indicate that RV-induced TGF-β1 secretion in COPD AEC attenuates the innate immune responses required for optimal clearing of bacteria by pulmonary macrophages and, this may increase the risk for acquiring secondary bacterial infections. At the same time, secretome from RV-infected COPD AEC may also increase inflammation via enhancing the bacteria-induced pro-inflammatory cytokines.