Pharmacological NKT cell activation using KRN7000 reduced collagen deposition and ameliorated vascular remodeling in models of pulmonary hypertension caused by lung fibrosis.
Does NKT cell activation reduce vascular fibrosis and improve hemodynamics in pulmonary hypertension caused by lung fibrosis?
Activation of NKT cells and the subsequent STAT1-CXCL9-CXCR3 axis represents a potential novel therapeutic strategy to target vascular fibrosis in pulmonary hypertension associated with interstitial lung disease.
Abstract Rationale Pulmonary hypertension (PH) is a common, severe comorbidity in interstitial lung diseases such as pulmonary fibrosis (PF), and it has limited treatment options. Excessive vascular fibrosis and inflammation are often present in PH, but the underlying mechanisms are still not well understood. Objectives To identify a novel functional link between natural killer T (NKT) cell activation and vascular fibrosis in PF-PH. Methods Multicolor flow cytometry, secretome, and immunohistological analyses were complemented by pharmacological NKT cell activation in vivo, in vitro, and ex vivo. Measurements and Main Results In pulmonary vessels of patients with PF-PH, increased collagen deposition was linked to a local NKT cell deficiency and decreased IL-15 concentrations. In a mouse model of PH caused by lung fibrosis, pharmacological NKT cell activation using a synthetic α-galactosylceramide analog (KRN7000) restored local NKT cell numbers and ameliorated vascular remodeling and right ventricular systolic pressure. Supplementation with activated NKT cells reduced collagen deposition in isolated human pulmonary arterial smooth muscle cells (hPASMCs) and in ex vivo precision-cut lung slices of patients with end-stage PF-PH. Coculture with activated NKT cells induced STAT1 signaling in hPASMCs. Secretome analysis of peripheral blood mononuclear cells identified CXCL9 and CXCL10 as indicators of NKT cell activation. Pharmacologically, CXCL9, but not CXCL10, potently inhibited collagen deposition in hPASMCs via the chemokine receptor CXCR3. Conclusions Our results indicate that the absence of NKT cells impairs the STAT1–CXCL9–CXCR3 axis in PF-PH and that restoration of this axis by NKT cell activation may unravel a novel therapeutic strategy to target vascular fibrosis in interstitial lung disease.
Jandl et al. (Tue,) conducted a other in Pulmonary hypertension caused by lung fibrosis. NKT cell activation (KRN7000) / CXCL9 was evaluated on Collagen deposition and vascular remodeling. Pharmacological NKT cell activation using KRN7000 reduced collagen deposition and ameliorated vascular remodeling in models of pulmonary hypertension caused by lung fibrosis.