Impaired Interleukin-15 Signaling via BMPR2 Loss Drives Natural Killer Cell Deficiency and Pulmonary Hypertension

Hypertension. 2022 Nov;79(11):2493-2504. doi: 10.1161/HYPERTENSIONAHA.122.19178. Epub 2022 Aug 31.


Background: Natural killer (NK) cell impairment is a feature of pulmonary arterial hypertension (PAH) and contributes to vascular remodeling in animal models of disease. Although mutations in BMPR2, the gene encoding the BMP (bone morphogenetic protein) type-II receptor, are strongly associated with PAH, the contribution of BMPR2 loss to NK cell impairment remains unknown. We explored the impairment of IL (interleukin)-15 signaling, a central mediator of NK cell homeostasis, as both a downstream target of BMPR2 loss and a contributor to the pathogenesis of PAH.

Methods: The expression, trafficking, and secretion of IL-15 and IL-15Rα (interleukin 15 α-type receptor) were assessed in human pulmonary artery endothelial cells, with or without BMPR2 silencing. NK cell development and IL-15/IL-15Rα levels were quantified in mice bearing a heterozygous knock-in of the R899X-BMPR2 mutation (bmpr2+/R899X). NK-deficient Il15-/- rats were exposed to the Sugen/hypoxia and monocrotaline models of PAH to assess the impact of impaired IL-15 signaling on disease severity.

Results: BMPR2 loss reduced IL-15Rα surface presentation and secretion in human pulmonary artery endothelial cells via impaired trafficking through the trans-Golgi network. bmpr2+/R899X mice exhibited a decrease in NK cells, which was not attributable to impaired hematopoietic development but was instead associated with reduced IL-15/IL-15Rα levels in these animals. Il15-/- rats of both sexes exhibited enhanced disease severity in the Sugen/hypoxia model, with only male Il15-/- rats developing more severe PAH in response to monocrotaline.

Conclusions: This work identifies the loss of IL-15 signaling as a novel BMPR2-dependent contributor to NK cell impairment and pulmonary vascular disease.

Keywords: BMPR2 receptor; NK cells; endothelial cells; inflammation; interleukin-15; pulmonary arterial hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Bone Morphogenetic Protein Receptors, Type II / metabolism
  • Endothelial Cells / metabolism
  • Female
  • GATA2 Deficiency* / complications
  • GATA2 Deficiency* / metabolism
  • GATA2 Deficiency* / pathology
  • Humans
  • Hypertension, Pulmonary* / etiology
  • Hypoxia / metabolism
  • Interleukin-15 / genetics
  • Interleukin-15 / metabolism
  • Male
  • Mice
  • Monocrotaline
  • Pulmonary Arterial Hypertension*
  • Pulmonary Artery / metabolism
  • Rats


  • Interleukin-15
  • Monocrotaline
  • Bone Morphogenetic Protein Receptors, Type II
  • BMPR2 protein, human
  • Bmpr2 protein, rat