Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency

Matthew T. Rätsep, Stephen D. Moore, Salema Jafri, Melissa Mitchell, Hugh J.M. Brady, Ofer Mandelboim, Mark Southwood, Nicholas W. Morrell, Francesco Colucci, Mark L. Ormiston*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Natural killer (NK) cells are cytotoxic innate lymphoid cells with an established role in the regulation of vascular structure in pregnancy and cancer. Impaired NK cell function has been identified in patients with pulmonary arterial hypertension (PAH), a disease of obstructive vascular remodeling in the lungs, as well as in multiple rodent models of disease. However, the precise contribution of NK cell impairment to the initiation and progression of PAH remains unknown. Here, we report the development of spontaneous pulmonary hypertension in two independent genetic models of NK cell dysfunction, including Nfil3 / mice, which are deficient in NK cells due to the absence of the NFIL3 transcription factor, and Ncr1-Gfp mice, which lack the NK activating receptor NKp46. Mouse models of NK insufficiency exhibited increased right ventricular systolic pressure and muscularization of the pulmonary arteries in the absence of elevated left ventricular end-diastolic pressure, indicating that the development of pulmonary hypertension was not secondary to left heart dysfunction. In cases of severe NK cell impairment or loss, a subset of mice failed to develop pulmonary hypertension and instead exhibited reduced systemic blood pressure, demonstrating an extension of vascular abnormalities beyond the pulmonary circulation into the systemic vasculature. In both mouse models, the development of PAH was linked to elevated interleukin-23 production, whereas systemic hypotension in Ncr1-Gfp mice was accompanied by a loss of angiopoietin-2. Together, these results support an important role for NK cells in the regulation of pulmonary and systemic vascular function and the pathogenesis of PAH.

Original languageAmerican English
Pages (from-to)L977-L990
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume315
Issue number6
DOIs
StatePublished - Dec 2018

Bibliographical note

Publisher Copyright:
© 2018 the American Physiological Society.

Keywords

  • Angiopoietin-2
  • Interleukin-23
  • Natural killer cells
  • Pulmonary hypertension
  • Th17

Fingerprint

Dive into the research topics of 'Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency'. Together they form a unique fingerprint.

Cite this