Date Published: December 1, 2018
Publisher: American Physiological Society
Author(s): 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.
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.
Natural killer (NK) cells are innate lymphoid cells (ILCs) that are traditionally charged with the identification and lysis of stressed, oncogenically transformed, or virally infected cells. Beyond this role as the cytotoxic effectors of innate immunity, multiple reports have also highlighted a role for NK cells in the regulation of vascular structure, integrity, and tone (6, 19, 42, 48). This vascular activity has been particularly well documented in pregnancy, where NK cells in the decidual lining of the pregnant uterus are believed to influence the expansion of the spiral arteries that supply oxygen and nutrients to the developing fetus (3, 19, 26). Although this functionality was originally believed to be limited to the specialized NK cells of the uterus, recent studies have demonstrated a potential role for NK cells in the regulation of other vascular beds (6, 23, 48), including the pulmonary circulation (31, 49).
We report the spontaneous development of PH in two genetic models of NK cell insufficiency, NK cell-deficient Nfil3−/− mice and Ncr1+/gfp mice, which are heterozygous for the NK activating receptor NKp46. In both models, PH was observed in the absence of elevated LVEDP, indicating that the increases in RV pressures were not secondary to venous congestion resulting from left heart failure. In contrast, our assessment of systemic blood pressure identified abnormalities exclusively in mice with seemingly normal pulmonary vascular pressures, including the subset of aged Nfil3−/− mice that failed to develop elevated RVSP with age and Ncr1gfp/gfp mice, which completely lack NKp46. Both of these groups exhibited a marked reduction in systemic blood pressure, suggesting a model whereby moderate NK cell dysfunction can result in PH, whereas severe NK cell impairment causes vascular dysfunction that extends to the systemic circulation, resulting in reduced systemic blood pressure and preventing the manifestation of elevated pressures in the pulmonary circulation.
This work was funded through Canadian Institutes of Health Research Project Grant PJT-152916 and British Heart Foundation Fellowship FS/12/39/29653.
No conflicts of interest, financial or otherwise, are declared by the authors.
M.L.O. conceived and designed research; M.T.R., S.D.M., S.J., M.M., M.S., and M.L.O. performed experiments; M.T.R., S.D.M., and M.L.O. analyzed data; M.T.R., S.D.M., and M.L.O. interpreted results of experiments; M.T.R. and M.L.O. prepared figures; M.T.R. and M.L.O. drafted manuscript; M.T.R., H.J.M.B., O.M., N.W.M., F.C., and M.L.O. edited and revised manuscript; M.T.R., S.D.M., S.J., H.J.M.B., O.M., M.S., N.W.M., F.C., and M.L.O. approved final version of manuscript.