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Impairment of the NKT–STAT1–CXCL9 Axis Contributes to Vessel Fibrosis in Pulmonary Hypertension Caused by Lung Fibrosis

Jandl, Katharina ; Marsh, Leigh M. ; Mutgan, Ayse Ceren LU orcid ; Crnkovic, Slaven ; Valzano, Francesco ; Zabini, Diana ; Hoffmann, Julia ; Foris, Vasile ; Gschwandtner, Elisabeth and Klepetko, Walter , et al. (2022) In American Journal of Respiratory and Critical Care Medicine 206(8). p.981-998
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 immuno-histological 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... (More)

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 immuno-histological 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 a-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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
immunotherapy, interstitial lung disease, vascular fibrosis, vascular remodeling
in
American Journal of Respiratory and Critical Care Medicine
volume
206
issue
8
pages
18 pages
publisher
American Thoracic Society
external identifiers
  • scopus:85139293460
  • pmid:35763380
ISSN
1073-449X
DOI
10.1164/RCCM.202201-0142OC
language
English
LU publication?
no
additional info
Publisher Copyright: Copyright © 2022 by the American Thoracic Society.
id
7eb81228-2010-4a54-9d8e-c008835b2171
date added to LUP
2025-03-20 13:59:45
date last changed
2025-07-10 22:43:18
@article{7eb81228-2010-4a54-9d8e-c008835b2171,
  abstract     = {{<p>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 immuno-histological 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 a-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.</p>}},
  author       = {{Jandl, Katharina and Marsh, Leigh M. and Mutgan, Ayse Ceren and Crnkovic, Slaven and Valzano, Francesco and Zabini, Diana and Hoffmann, Julia and Foris, Vasile and Gschwandtner, Elisabeth and Klepetko, Walter and Prosch, Helmut and Flick, Holger and Brcic, Luka and Kern, Izidor and Heinemann, Akos and Olschewski, Horst and Kovacs, Gabor and Kwapiszewska, Grazyna}},
  issn         = {{1073-449X}},
  keywords     = {{immunotherapy; interstitial lung disease; vascular fibrosis; vascular remodeling}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{8}},
  pages        = {{981--998}},
  publisher    = {{American Thoracic Society}},
  series       = {{American Journal of Respiratory and Critical Care Medicine}},
  title        = {{Impairment of the NKT–STAT1–CXCL9 Axis Contributes to Vessel Fibrosis in Pulmonary Hypertension Caused by Lung Fibrosis}},
  url          = {{http://dx.doi.org/10.1164/RCCM.202201-0142OC}},
  doi          = {{10.1164/RCCM.202201-0142OC}},
  volume       = {{206}},
  year         = {{2022}},
}