RATIONALE: Pulmonary hypertension (PH) is a common, yet severe comorbidity in interstitial lung diseases (ILD) such as pulmonary fibrosis (PF), with limited treatment options. Excessive vascular fibrosis and inflammation are often present in PH, but the underlying mechanisms are still not well understood. OBJECTIVE: 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 immuno-histological analysis were complemented by pharmacological NKT-cell activation in-vivo, in-vitro and ex-vivo. MEASUREMENTS AND MAIN RESULTS: In pulmonary vessels of PF-PH patients increased collagen deposition was linked to a local NKT cell deficiency and decreased interleukin-15 levels. In a mouse model of PH due to 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 (hPASMC) and in ex-vivo precision-cut lung slices of end-stage PF-PH patients. Co-culture with activated NKT cells induced STAT1 signaling in hPASMC. Secretome analysis of peripheral blood mononuclear cells (PBMCs) identified CXCL9 and CXCL10 as indicators of NKT cell activation. Pharmacologically, CXCL9, but not CXCL10, potently inhibited collagen deposition in hPASMC via the chemokine receptor, CXCR3. CONCLUSION: 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 ILD.
- Jandl, K.
- Marsh, L. M.
- Mutgan, A. C.
- Crnkovic, S.
- Valzano, F.
- Zabini, D.
- Hoffmann, J.
- Foris, V.
- Gschwandtner, E.
- Klepetko, W.
- Prosch, H.
- Flick, H.
- Brcic, L.
- Kern, I.
- Heinemann, A.
- Olschewski, H.
- Kovacs, G.
- Kwapiszewska, G.
Keywords
- immunotherapy
- interstitial lung disease
- vascular fibrosis
- vascular remodelling
