Impaired Interleukin-15 Signaling via BMPR2 Loss Drives Natural Killer Cell Deficiency and Pulmonary Hypertension. Issue 11 (31st August 2022)

• Record Type: Journal Article
• Authors: Hilton, L. Rhiannon; Rätsep, Matthew T.; VandenBroek, M. Martin; Jafri, Salema; Laverty, Kimberly J.; Mitchell, Melissa; Theilmann, Anne L.; Smart, James A.; Hawke, Lindsey G.; Moore, Stephen D.; Renaud, Stephen J.; Soares, Michael J.; Morrell, Nicholas W.; Ormiston, Mark L.
• Is Part Of: Hypertension. Volume 79:Issue 11(2022)
• Page Start: 2493
• Page End: 2504
• Publication Date: 2022-08-31
• Subjects: BMPR2 receptor -- endothelial cells -- inflammation -- interleukin-15 -- NK cells -- pulmonary arterial hypertension; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.122.19178
• Languages: English
• ISSNs: 0194-911X

Abstract

Abstract : 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.