1. Academic Validation
  2. Impairment of the NKT-STAT1-CXCL9-axis Contributes to Vessel Fibrosis in Pulmonary Hypertension Due to Lung Fibrosis

Impairment of the NKT-STAT1-CXCL9-axis Contributes to Vessel Fibrosis in Pulmonary Hypertension Due to Lung Fibrosis

  • Am J Respir Crit Care Med. 2022 Jun 28. doi: 10.1164/rccm.202201-0142OC.
Katharina Jandl 1 Leigh M Marsh 1 Ayse Ceren Mutgan 2 Slaven Crnkovic 3 Francesco Valzano 1 Diana Zabini 4 Julia Hoffmann 5 Vasile Foris 6 Elisabeth Gschwandtner 7 Walter Klepetko 8 Helmut Prosch 9 Holger Flick 10 Luka Brcic 11 Izidor Kern 12 Akos Heinemann 13 Horst Olschewski 14 Gabor Kovacs 10 Grazyna Kwapiszewska 15
Affiliations

Affiliations

  • 1 LBI for Lung Vascular Research, Graz, Austria.
  • 2 Medical University of Graz, 31475, Otto Loewi Research Center, Division of Physiology, Graz, Steiermark, Austria.
  • 3 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
  • 4 Medical University of Graz, Otto Loewi Research Center, Division of Physiology, Graz, Austria.
  • 5 Ludwig Boltzmann Institute for Lung Vascular Research , Graz, Austria.
  • 6 Medical University of Graz, Division of Pulmonology, Department of Internal Medicine, Graz, Austria.
  • 7 Medical University of Vienna, 27271, Department of Surgery, Vienna, Austria.
  • 8 Medical University of Vienna, 27271, Department of Surgery, Wien, Austria.
  • 9 Medical University of Vienna, Vienna, Austria.
  • 10 Medical University of Graz, 31475, Division of Pulmonology, Department of Internal Medicine, Graz, Austria.
  • 11 Medizinische Universitat Graz Institut fur Pathologie, 199405, Graz, Austria.
  • 12 University Clinic of Respiratory and Allergic Diseases Golnik, 68936, Cytology and Pathology Laboratory, Golnik, Slovenia.
  • 13 Medical University Graz, Instituite of Experimental and Clinical Pharmacology, Graz, Austria.
  • 14 Medical University of Graz, Department of Internal Medicine, Graz, Austria.
  • 15 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; [email protected].
Abstract

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.

Keywords

immunotherapy; interstitial lung disease; vascular fibrosis; vascular remodelling.

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