IL-17RA/RC blockade modulates the fibrinolytic system and MMP activity in bleomycin-induced pulmonary fibrosis in male mice.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with excessive accumulation of extracellular matrix (ECM) components, which leads to disrupted lung architecture and respiratory failure. Interleukin (IL)-17 signaling induces fibrosis through inflammation; however, specific roles of its receptors IL-1RA and IL-17RC in fibrinolysis and ECM remodeling remain unclear. We hypothesized that inhibition of either IL-17RA or IL-17RC could reduce fibrosis by regulating MMP expression and function. In this study, a Bleomycin (BLM)-induced murine model of pulmonary fibrosis was used to study the effect of neutralization of IL-17RA and IL-17RC on ECM remodeling, MMPs, and the fibrinolytic system. Fibrotic lungs showed increased levels of MMP-2 and MMP-9, corresponding with elevated expression of fibronectin and collagen. Neutralization of either IL-17RA or IL-17RC significantly reduced the expression of MMPs, activation of NF-κB, and restored normal fibrinolytic activity by upregulating uPA and downregulating PAI-1 levels.