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

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.

Fischer rats exhibit maladaptive structural and molecular right ventricular remodelling in severe pulmonary hypertension: a genetically prone model for right heart failure

“…Moreover, it has been reported that NOD-SCID mice exhibit poor functional recovery and revascularization following myocardial infarction compared with immune-competent mice, which can be rescued by adoptive transfer of IL-2 stimulated NK cells 13 . NK cells have also been implicated in the pathobiology of PAH 17 , 18 . Nfil3 − / − mice that lack NFIL3 transcription factor and Ncr1-GFP mice that lack the NK cell activating receptor exhibit NK cell deficiency and develop spontaneously develop PH 18 .…”

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

“…Furthermore, in two independent genetic mouse models for NK cell dysfunction, involving deficiency of the NFIL3 transcription factor or the NK activating receptor NKp46, enhanced RV systolic pressures and RV hypertrophy were found. In both models, this experimental PH development was linked to increased interleukin-23 (IL-23) production, possibly due to NK cells or impairment, leading to the increased production of IL-23 by pulmonary macrophages and other myeloid cell types [66]. Interestingly, IL-23 is known for its production of inflammatory cytokines, such as IL-17A/F, IL-21 and IL-22, and for driving naïve T cells to a TH17 phenotype [67].…”

Idiopathic pulmonary fibrosis and pulmonary hypertension: Heracles meets the Hydra

“…These findings linked the ACE2/Ang-(1-7)/Mas axis with inflammation, activation of the angiotensin type 2 receptor, attenuated BLM-induced lung fibrosis, vascular remodelling, and increased RVSP, concomitant with a reduction of infiltrated macrophages (Rathinasabapathy, Horowitz, et al, 2018). These mechanisms are summarized in Figure 1.…”