Club cell 10-kDa protein (CC10) inhibits cPLA2/COX2 pathway to alleviate RSV-induced airway inflammation and AHR

Respiratory syncytial virus (RSV) is the most common viral pathogen causing acute lower respiratory tract infections (LRTI) in infants. Airway epithelial cells, including Club cells, are primary targets of RSV infection. The "Club cell 10-kDa protein" (CC10), produced mainly by Club cells, possesses anti-inflammatory and immunoregulatory properties that are relevant in infection, injury, and allergic reactions. However, its role in the RSV infection is not fully understood. In the clinic, we found that levels of CC10 in the nasopharyngeal aspirates (NPA) of infants, hospitalized with RSV bronchiolitis, were significantly lower than those without LRTI, and were also negatively correlated with the severity of the disease. In BALB/c mice, the CC10 levels in the bronchoalveolar lavage fluid (BALF) were also decreased at the 5th day after infection. When recombinant CC10 was administrated in the mice, RSV-induced airway inflammation and airway hyperresponsiveness (AHR) were alleviated. Similarly, inhibition of cytosolic phospholipase A2 (cPLA2) or cyclooxygenase 2 (COX2), which is a downstream signaling molecule for cPLA2, both alleviated RSV-induced airway inflammation and AHR. Administration of CC10 reduced the phosphorylation of cPLA2 and protein levels of COX-2 in mouse lungs, resulting from infection, thus providing a molecular mechanism for previous reports that CC10 plays a protective role, partly through inhibiting the activity of cPLA2. We conclude that CC10 inhibits the cPLA2/COX2 pathway to alleviate RSV-induced lung airway inflammation and AHR.