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Immune mechanisms in the pathophysiology of hypertension

Nature Reviews Nephrology (2024)Cite this article

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Abstract

Hypertension is a leading risk factor for morbidity and mortality worldwide. Despite current anti-hypertensive therapies, most individuals with hypertension fail to achieve adequate blood pressure control. Moreover, even with adequate control, a residual risk of cardiovascular events and associated organ damage remains. These findings suggest that current treatment modalities are not addressing a key element of the underlying pathology. Emerging evidence implicates immune cells as key mediators in the development and progression of hypertension. In this Review, we discuss our current understanding of the diverse roles of innate and adaptive immune cells in hypertension, highlighting key findings from human and rodent studies. We explore mechanisms by which these immune cells promote hypertensive pathophysiology, shedding light on their multifaceted involvement. In addition, we highlight advances in our understanding of autoimmunity, HIV and immune checkpoints that provide valuable insight into mechanisms of chronic and dysregulated inflammation in hypertension.

Key points

  • Emerging evidence from human and rodent studies suggests an important role for both innate and adaptive immune cells in the pathogenesis of hypertension.

  • The release of inflammatory cytokines, production of reactive oxygen species, and neoantigen presentation by innate immune cells results in vascular damage, renal injury, inflammation and elevated blood pressure.

  • Adaptive immune cells shift towards pro-inflammatory roles in hypertension, resulting in enhanced cytotoxicity and inflammatory cytokine production that leads to impaired vascular and renal natriuretic functions.

  • Immune cells coordinate as an integrated system, suggesting that targeting regulatory nodes of the inflammatory response might be beneficial for treating hypertension.

  • Current evidence supports a model whereby immune activation and resultant hypertension-related organ dysfunction act synergistically to amplify blood pressure and promote end-organ damage in hypertension.

  • Advances in our understanding of autoimmunity, HIV and immune checkpoint inhibitor therapies provide key insights into the effects of immune activation and chronic inflammation in the development of hypertension.

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Fig. 1: Multiple hypertensive stimuli activate innate immune cells to promote inflammation leading to blood pressure elevations and end organ damage.
Fig. 2: Multiple stimuli including innate immune cells activate T cells to promote hypertension development and related end-organ damage.

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References

  1. GBD 2015 Risk Factors Collaborators Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388, 1659–1724 (2016).

    Article  Google Scholar 

  2. Whelton, P. K. et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 138, e426–e483 (2018).

    PubMed  Google Scholar 

  3. Muntner, P. et al. Trends in blood pressure control among US adults with hypertension, 1999–2000 to 2017–2018. JAMA 324, 1190–1200 (2020).

    Article  PubMed  Google Scholar 

  4. Newton, K. & Dixit, V. M. Signaling in innate immunity and inflammation. Cold Spring Harb. Perspect. Biol. 4, a006049 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Guzik, T. J. et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J. Exp. Med. 204, 2449–2460 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Marko, L. et al. Interferon-γ signaling inhibition ameliorates angiotensin II-induced cardiac damage. Hypertension 60, 1430–1436 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Wei, S. Y. et al. Multiple mechanisms are involved in salt-sensitive hypertension-induced renal injury and interstitial fibrosis. Sci. Rep. 7, 45952 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xiao, L. et al. Renal denervation prevents immune cell activation and renal inflammation in angiotensin II-induced hypertension. Circ. Res. 117, 547–557 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Madhur, M. S. et al. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension 55, 500–507 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Wenzel, P. Monocytes as immune targets in arterial hypertension. Br. J. Pharmacol. 176, 1966–1977 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Parissis, J. T., Korovesis, S., Giazitzoglou, E., Kalivas, P. & Katritsis, D. Plasma profiles of peripheral monocyte-related inflammatory markers in patients with arterial hypertension. Correlations with plasma endothelin-1. Int. J. Cardiol. 83, 13–21 (2002).

    Article  PubMed  Google Scholar 

  12. Alexander, M. R. et al. Human monocyte transcriptional profiling identifies IL-18 receptor accessory protein and lactoferrin as novel immune targets in hypertension. Br. J. Pharmacol. 176, 2015–2027 (2019).

    Article  CAS  PubMed  Google Scholar 

  13. Kirabo, A. et al. DC isoketal-modified proteins activate T cells and promote hypertension. J. Clin. Invest. 124, 4642–4656 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Loperena, R. et al. Hypertension and increased endothelial mechanical stretch promote monocyte differentiation and activation: roles of STAT3, interleukin 6 and hydrogen peroxide. Cardiovasc. Res. 114, 1547–1563 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wenzel, P. et al. Lysozyme M-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction. Circulation 124, 1370–1381 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Kossmann, S. et al. Inflammatory monocytes determine endothelial nitric-oxide synthase uncoupling and nitro-oxidative stress induced by angiotensin II. J. Biol. Chem. 289, 27540–27550 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gkaliagkousi, E. et al. Decreased platelet nitric oxide contributes to increased circulating monocyte-platelet aggregates in hypertension. Eur. Heart J. 30, 3048–3054 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Zaldivia, M. T. et al. Renal denervation reduces monocyte activation and monocyte-platelet aggregate formation: an anti-inflammatory effect relevant for cardiovascular risk. Hypertension 69, 323–331 (2017).

    Article  CAS  PubMed  Google Scholar 

  19. Han, P. et al. Platelet P-selectin initiates cross-presentation and dendritic cell differentiation in blood monocytes. Sci. Adv. 6, eaaz1580 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gebhard, S. et al. Angiotensin II-dependent hypertension causes reversible changes in the platelet proteome. J. Hypertens. 29, 2126–2137 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Hilt, Z. T. et al. Platelet-derived β2M regulates monocyte inflammatory responses. JCI Insight 4, e122943 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hughson, M. D. et al. Associations of glomerular number and birth weight with clinicopathological features of African Americans and whites. Am. J. Kidney Dis. 52, 18–28 (2008).

    Article  PubMed  Google Scholar 

  23. De Ciuceis, C. et al. Reduced vascular remodeling, endothelial dysfunction, and oxidative stress in resistance arteries of angiotensin II-infused macrophage colony-stimulating factor-deficient mice: evidence for a role in inflammation in angiotensin-induced vascular injury. Arterioscler. Thromb. Vasc. Biol. 25, 2106–2113 (2005).

    Article  PubMed  Google Scholar 

  24. Oh, J. et al. Macrophage secretion of miR-106b-5p causes renin-dependent hypertension. Nat. Commun. 11, 4798 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ip, W. K. & Medzhitov, R. Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation. Nat. Commun. 6, 6931 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Machnik, A. et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat. Med. 15, 545–552 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Thowsen, I. M. et al. Genetic engineering of lymphangiogenesis in skin does not affect blood pressure in mouse models of salt-sensitive hypertension. Hypertension 79, 2451–2462 (2022).

    Article  CAS  PubMed  Google Scholar 

  28. Shah, K. H. et al. Myeloid suppressor cells accumulate and regulate blood pressure in hypertension. Circ. Res. 117, 858–869 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vinh, A. et al. Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension. Circulation 122, 2529–2537 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Barbaro, N. R. et al. Dendritic cell amiloride-sensitive channels mediate sodium-induced inflammation and hypertension. Cell Rep. 21, 1009–1020 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Van Beusecum, J. P. et al. High salt activates CD11c+ antigen-presenting cells via SGK (Serum Glucocorticoid Kinase) 1 to promote renal inflammation and salt-sensitive hypertension. Hypertension 74, 555–563 (2019).

    Article  PubMed  Google Scholar 

  32. Van Beusecum, J. P. et al. Growth arrest specific-6 and Axl coordinate inflammation and hypertension. Circ. Res. 129, 975–991 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Thiam, H. R., Wong, S. L., Wagner, D. D. & Waterman, C. M. Cellular mechanisms of NETosis. Annu. Rev. Cell Dev. Biol. 36, 191–218 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tatsukawa, Y. et al. White blood cell count, especially neutrophil count, as a predictor of hypertension in a Japanese population. Hypertens. Res. 31, 1391–1397 (2008).

    Article  PubMed  Google Scholar 

  35. Siedlinski, M. et al. White blood cells and blood pressure: a Mendelian randomization study. Circulation 141, 1307–1317 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ramasamy, R., Maqbool, M., Mohamed, A. L. & Noah, R. M. Elevated neutrophil respiratory burst activity in essential hypertensive patients. Cell Immunol. 263, 230–234 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Folco, E. J. et al. Neutrophil extracellular traps induce endothelial cell activation and tissue factor production through interleukin-1ɑ and cathepsin G. Arterioscler. Thromb. Vasc. Biol. 38, 1901–1912 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kahlenberg, J. M., Carmona-Rivera, C., Smith, C. K. & Kaplan, M. J. Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J. Immunol. 190, 1217–1226 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Chrysanthopoulou, A. et al. Angiotensin II triggers release of neutrophil extracellular traps, linking thromboinflammation with essential hypertension. JCI Insight 6, e148668 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Krishnan, J. et al. IsoLGs (Isolevuglandins) drive neutrophil migration in hypertension and are essential for the formation of neutrophil extracellular traps. Hypertension 79, 1644–1655 (2022).

    Article  CAS  PubMed  Google Scholar 

  41. Ge, W. et al. The role of immunoglobulin E and mast cells in hypertension. Cardiovasc. Res. 118, 2985–2999 (2022).

    Article  CAS  PubMed  Google Scholar 

  42. Abais-Battad, J. M., Lund, H., Fehrenbach, D. J., Dasinger, J. H. & Mattson, D. L. Rag1-null Dahl SS rats reveal that adaptive immune mechanisms exacerbate high protein-induced hypertension and renal injury. Am. J. Physiol. Regul. Integr. Comp. Physiol. 315, R28–r35 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rudemiller, N., Lund, H., Jacob, H. J., Geurts, A. M. & Mattson, D. L. CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney. Hypertension 63, 559–564 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Crowley, S. D. et al. Lymphocyte responses exacerbate angiotensin II-dependent hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R1089–R1097 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Trott, D. W. et al. Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Hypertension 64, 1108–1115 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Sun, X. N. et al. T-cell mineralocorticoid receptor controls blood pressure by regulating interferon-γ. Circ. Res. 120, 1584–1597 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Strioga, M., Pasukoniene, V. & Characiejus, D. CD8+ CD28− and CD8+ CD57+ T cells and their role in health and disease. Immunology 134, 17–32 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Guan, Y. et al. CD28null T cells in aging and diseases: from biology to assessment and intervention. Int. Immunopharmacol. 131, 111807 (2024).

    Article  CAS  PubMed  Google Scholar 

  49. Dale, B. L. et al. Critical role of Interleukin 21 and T follicular helper cells in hypertension and vascular dysfunction. JCI Insight 5, e129278 (2019).

    Article  PubMed  Google Scholar 

  50. Itani, H. A. et al. Activation of human T cells in hypertension: studies of humanized mice and hypertensive humans. Hypertension 68, 123–132 (2016).

    Article  CAS  PubMed  Google Scholar 

  51. Higaki, A., Mahmoud, A. U. M., Paradis, P. & Schiffrin, E. L. Role of interleukin-23/interleukin-17 axis in T-cell-mediated actions in hypertension. Cardiovasc. Res. 117, 1274–1283 (2021).

    Article  CAS  PubMed  Google Scholar 

  52. Kamat, N. V. et al. Renal transporter activation during angiotensin-II hypertension is blunted in interferon-γ−/− and interleukin-17A−/− mice. Hypertension 65, 569–576 (2015).

    Article  CAS  PubMed  Google Scholar 

  53. Liu, Y. et al. CD8+ T cells stimulate Na-Cl co-transporter NCC in distal convoluted tubules leading to salt-sensitive hypertension. Nat. Commun. 8, 14037 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yao, W., Sun, Y., Wang, X. & Niu, K. Elevated serum level of interleukin 17 in a population with prehypertension. J. Clin. Hypertens. 17, 770–774 (2015).

    Article  CAS  Google Scholar 

  55. Nguyen, H. et al. Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension. Cardiovasc. Res. 97, 696–704 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Wu, J. et al. Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ. Res. 114, 616–625 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Orejudo, M. et al. Interleukin-17A induces vascular remodeling of small arteries and blood pressure elevation. Clin. Sci. 134, 513–527 (2020).

    Article  CAS  Google Scholar 

  58. Orejudo, M. et al. Interleukin 17A participates in renal inflammation associated to experimental and human hypertension. Front. Pharmacol. 10, 1015 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Norlander, A. E. et al. Interleukin-17A regulates renal sodium transporters and renal injury in angiotensin II-induced hypertension. Hypertension 68, 167–174 (2016).

    Article  CAS  PubMed  Google Scholar 

  60. Boehm, U., Klamp, T., Groot, M. & Howard, J. C. Cellular responses to interferon-γ. Annu. Rev. Immunol. 15, 749–795 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Garcia, A. G. et al. Interferon-γ ablation exacerbates myocardial hypertrophy in diastolic heart failure. Am. J. Physiol. Heart Circ. Physiol. 303, H587–H596 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kimura, A. et al. Protective roles of interferon-γ in cardiac hypertrophy induced by sustained pressure overload. J. Am. Heart Assoc. 7, e008145 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Benson, L. N. et al. The IFNγ-PDL1 pathway enhances CD8T-DCT interaction to promote hypertension. Circ. Res. 130, 1550–1564 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Saleh, M. A. et al. Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation. J. Clin. Invest. 125, 1189–1202 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Zhang, J. et al. Tumor necrosis factor-ɑ produced in the kidney contributes to angiotensin II-dependent hypertension. Hypertension 64, 1275–1281 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Hsieh, C. S., Macatonia, S. E., O’Garra, A. & Murphy, K. M. T cell genetic background determines default T helper phenotype development in vitro. J. Exp. Med. 181, 713–721 (1995).

    Article  CAS  PubMed  Google Scholar 

  67. Wang, X. et al. Relationship of serum immunoglobulin levels to blood pressure and hypertension in an adult population. J. Hum. Hypertens. 32, 212–218 (2018).

    Article  CAS  PubMed  Google Scholar 

  68. Chen, Y. et al. Class switching and high-affinity immunoglobulin G production by B cells is dispensable for the development of hypertension in mice. Cardiovasc. Res. 117, 1217–1228 (2021). PMC7983008.

    Article  CAS  PubMed  Google Scholar 

  69. Chan, C. T. et al. Obligatory role for B cells in the development of angiotensin II-dependent hypertension. Hypertension 66, 1023–1033 (2015).

    Article  CAS  PubMed  Google Scholar 

  70. Lei, L., Zhong, X. N., He, Z. Y., Zhao, C. & Sun, X. J. IL-21 induction of CD4+ T cell differentiation into Th17 cells contributes to bleomycin-induced fibrosis in mice. Cell Biol. Int. 39, 388–399 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Rudensky, A. Y. Regulatory T cells and Foxp3. Immunol. Rev. 241, 260–268 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Valencia, X. & Lipsky, P. E. CD4+CD25+FoxP3+ regulatory T cells in autoimmune diseases. Nat. Clin. Pract. Rheumatol. 3, 619–626 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Kvakan, H. et al. Regulatory T cells ameliorate angiotensin II-induced cardiac damage. Circulation 119, 2904–2912 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Barhoumi, T. et al. T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury. Hypertension 57, 469–476 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Tipton, A. J., Baban, B. & Sullivan, J. C. Female spontaneously hypertensive rats have greater renal anti-inflammatory T lymphocyte infiltration than males. Am. J. Physiol. Regul. Integr. Comp. Physiol. 303, R359–R367 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gillis, E. E., Musall, J. B., Baban, B. & Sullivan, J. C. IL-10 treatment decreases blood pressure in male, but not female, spontaneously hypertensive rats. Am. J. Physiol. Renal Physiol. 319, F359–F365 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Mian, M. O., Barhoumi, T., Briet, M., Paradis, P. & Schiffrin, E. L. Deficiency of T-regulatory cells exaggerates angiotensin II-induced microvascular injury by enhancing immune responses. J. Hypertens. 34, 97–108 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Emmerson, A. et al. Nox2 in regulatory T cells promotes angiotensin II-induced cardiovascular remodeling. J. Clin. Invest. 128, 3088–3101 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Kasal, D. A. et al. T regulatory lymphocytes prevent aldosterone-induced vascular injury. Hypertension 59, 324–330 (2012).

    Article  CAS  PubMed  Google Scholar 

  81. Matrougui, K. et al. Natural regulatory T cells control coronary arteriolar endothelial dysfunction in hypertensive mice. Am. J. Pathol. 178, 434–441 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gackowska, L. et al. Regulatory T-cell subset distribution in children with primary hypertension is associated with hypertension severity and hypertensive target organ damage. J. Hypertens. 38, 692–700 (2020).

    Article  CAS  PubMed  Google Scholar 

  83. Sawant, D. V. & Vignali, D. A. Once a Treg, always a Treg? Immunol. Rev. 259, 173–191 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hernandez, A. L. et al. Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. J. Clin. Invest. 125, 4212–4222 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Kleinewietfeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518–522 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Alexander, M. R. et al. Immune profiling reveals decreases in circulating regulatory and exhausted T cells in human hypertension. JACC Basic. Transl. Sci. 8, 319–336 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Fabbiano, S. et al. Immunosuppression-independent role of regulatory T cells against hypertension-driven renal dysfunctions. Mol. Cell Biol. 35, 3528–3546 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Shokoples, B. G. et al. P2RX7 gene knockout or antagonism reduces angiotensin II-induced hypertension, vascular injury and immune cell activation. J. Hypertens. 41, 1701–1712 (2023).

    Article  CAS  PubMed  Google Scholar 

  89. Junger, W. G. Immune cell regulation by autocrine purinergic signalling. Nat. Rev. Immunol. 11, 201–212 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhao, T. V. et al. ATP release drives heightened immune responses associated with hypertension. Sci. Immunol. 4, eaau6426 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Schenk, U. et al. ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci. Signal. 4, ra12 (2011).

    Article  PubMed  Google Scholar 

  92. MacLeod, M. K., Kappler, J. W. & Marrack, P. Memory CD4 T cells: generation, reactivation and re-assignment. Immunology 130, 10–15 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Itani, H. A. et al. CD70 exacerbates blood pressure elevation and renal damage in response to repeated hypertensive stimuli. Circ. Res. 118, 1233–1243 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Xiao, L., do Carmo, L. S., Foss, J. D., Chen, W. & Harrison, D. G. Sympathetic enhancement of memory T-cell homing and hypertension sensitization. Circ. Res. 126, 708–721 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ribot, J. C., Lopes, N. & Silva-Santos, B.γδ T cells in tissue physiology and surveillance. Nat. Rev. Immunol. 21, 221–232 (2021).

    Article  CAS  PubMed  Google Scholar 

  96. Caillon, A. et al. γδ T cells mediate angiotensin II-induced hypertension and vascular injury. Circulation 135, 2155–2162 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Comeau, K., Shokoples, B., Caillon, A., Paradis, P. & Schiffrin, E. L. Angiotensin II-induced memory γδ T cells sensitize mice to a mild hypertensive stimulus. Am. J. Hypertens. 36, 619–628 (2023).

    Article  CAS  PubMed  Google Scholar 

  98. Mamedov, M. R. et al. CRISPR screens decode cancer cell pathways that trigger γδ T cell detection. Nature 621, 188–195 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Harly, C. et al. Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset. Blood 120, 2269–2279 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Murakata, Y., Fujimaki, T. & Yamada, Y. Association of a butyrophilin, subfamily 2, member A1 gene polymorphism with hypertension. Biomed. Rep. 2, 818–822 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. Sonnenberg, G. F. & Hepworth, M. R. Functional interactions between innate lymphoid cells and adaptive immunity. Nat. Rev. Immunol. 19, 599–613 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Shah, A. S. V. et al. Global burden of atherosclerotic cardiovascular disease in people living with HIV: systematic review and meta-analysis. Circulation 138, 1100–1112 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Peck, R. N. et al. Hypertension, kidney disease, HIV and antiretroviral therapy among Tanzanian adults: a cross-sectional study. BMC Med. 12, 125 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Reis, K. G. et al. Blood pressure, T cells, and mortality in people with HIV in Tanzania during the first 2 years of antiretroviral therapy. J. Clin. Hypertens. 22, 1554–1562 (2020).

    Article  CAS  Google Scholar 

  106. Brenchley, J. M., Price, D. A. & Douek, D. C. HIV disease: fallout from a mucosal catastrophe? Nat. Immunol. 7, 235–239 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Wang, Y. et al. HIV-1-induced cytokines deplete homeostatic innate lymphoid cells and expand TCF7-dependent memory NK cells. Nat. Immunol. 21, 274–286 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Cerwenka, A. & Lanier, L. L. Natural killer cell memory in infection, inflammation and cancer. Nat. Rev. Immunol. 16, 112–123 (2016).

    Article  CAS  PubMed  Google Scholar 

  109. van den Boorn, J. G. et al. Inflammasome-dependent induction of adaptive NK cell memory. Immunity 44, 1406–1421 (2016).

    Article  PubMed  Google Scholar 

  110. Pitzer, A. et al. DC ENaC-dependent inflammasome activation contributes to salt-sensitive hypertension. Circ. Res. 131, 328–344 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Omi, T. et al. An intronic variable number of tandem repeat polymorphisms of the cold-induced autoinflammatory syndrome 1 (CIAS1) gene modifies gene expression and is associated with essential hypertension. Eur. J. Hum. Genet. 14, 1295–1305 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. Pontillo, A. et al. Polymorphisms in inflammasome genes and susceptibility to HIV-1 infection. J. Acquir. Immune Defic. Syndr. 59, 121–125 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Weng, N. P., Akbar, A. N. & Goronzy, J. CD28− T cells: their role in the age-associated decline of immune function. Trends Immunol. 30, 306–312 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tassiopoulos, K. et al. CD28-negative CD4+ and CD8+ T cells in antiretroviral therapy-naive HIV-infected adults enrolled in adult clinical trials group studies. J. Infect. Dis. 205, 1730–1738 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Morris, S. R. et al. Inflammescent CX3CR1+CD57+CD8+ T cells are generated and expanded by IL-15. JCI Insight 5, e132963 (2020).

    PubMed  PubMed Central  Google Scholar 

  116. Youn, J. C. et al. Immunosenescent CD8+ T cells and C-X-C chemokine receptor type 3 chemokines are increased in human hypertension. Hypertension 62, 126–133 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. Wei, S. C., Duffy, C. R. & Allison, J. P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8, 1069–1086 (2018).

    Article  PubMed  Google Scholar 

  118. Drobni, Z. D. et al. Association between immune checkpoint inhibitors with cardiovascular events and atherosclerotic plaque. Circulation 142, 2299–2311 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Turker, I., Sharma, A., Huang, S., Johnson, D. B. & Alexander, M. R. Combination immune checkpoint inhibitor therapy is associated with increased blood pressure in melanoma patients. Hypertension 80, e43–e45 (2022).

    PubMed  Google Scholar 

  120. Panoulas, V. F. et al. Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis. Rheumatology 46, 1477–1482 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Mirghani, H. et al. The association of psoriasis, diabetes mellitus, and hypertension: a meta-analysis. Cureus 15, e48855 (2023).

    PubMed  PubMed Central  Google Scholar 

  122. Manzi, S. et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am. J. Epidemiol. 145, 408–415 (1997).

    Article  CAS  PubMed  Google Scholar 

  123. Patrick, D. M. et al. Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus. JCI Insight 7, e136678 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Mathis, K. W. et al. Oxidative stress promotes hypertension and albuminuria during the autoimmune disease systemic lupus erythematosus. Hypertension 59, 673–679 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Rudofsky, U. H. et al. Differences in the occurrence of hypertension among (NZB X NZW)F1, MRL-lpr, and BXSB mice with lupus nephritis. Am. J. Pathol. 116, 107–114 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Clemmer, J. S., Hillegass, W. B. & Taylor, E. B. Antihypertensive effects of immunosuppressive therapy in autoimmune disease. J. Hum. Hypertens. 37, 300–306 (2023).

    Article  CAS  PubMed  Google Scholar 

  127. Herrera, J., Ferrebuz, A., MacGregor, E. G. & Rodriguez-Iturbe, B. Mycophenolate mofetil treatment improves hypertension in patients with psoriasis and rheumatoid arthritis. J. Am. Soc. Nephrol. 17, S218–S225 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Yoshida, S. et al. Infliximab, a TNF-ɑ inhibitor, reduces 24-h ambulatory blood pressure in rheumatoid arthritis patients. J. Hum. Hypertens. 28, 165–169 (2014).

    Article  CAS  PubMed  Google Scholar 

  129. Madhur, M. S. et al. Hypertension: do inflammation and immunity hold the key to solving this epidemic? Circ. Res. 128, 908–933 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Lieb, W., Enserro, D. M., Sullivan, L. M. & Vasan, R. S. Residual cardiovascular risk in individuals on blood pressure-lowering treatment. J. Am. Heart Assoc. 4, e002155 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Blacher, J. et al. Residual cardiovascular risk in treated hypertension and hyperlipidaemia: the PRIME study. J. Hum. Hypertens. 24, 19–26 (2010).

    Article  CAS  PubMed  Google Scholar 

  132. Bellamy, L., Casas, J.-P., Hingorani, A. D. & Williams, D. J. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 335, 974 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

    Bianca A. Nguyen, Matthew R. Alexander & David G. Harrison

  2. Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA

    Matthew R. Alexander & David G. Harrison

  3. Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Matthew R. Alexander & David G. Harrison

  4. Vanderbilt Institute for Infection, Immunology and Inflammation, Nashville, TN, USA

    Matthew R. Alexander & David G. Harrison

  5. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

    David G. Harrison

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Nguyen, B.A., Alexander, M.R. & Harrison, D.G. Immune mechanisms in the pathophysiology of hypertension. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00838-w

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