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Innate immunity and clinical hypertension


Emerging evidence has supported a role of inflammation and immunity in the genesis of hypertension. In humans and experimental models of hypertension, cells of the innate and adaptive immune system enter target tissues, including vessels and the kidney, and release powerful mediators including cytokines, matrix metalloproteinases and reactive oxygen species that cause tissue damage, fibrosis and dysfunction. These events augment the blood pressure elevations in hypertension and promote end-organ damage. Factors that activate immune cells include sympathetic outflow, increased sodium within microenvironments where these cells reside, and signals received from the vasculature. In particular, the activated endothelium releases reactive oxygen species and interleukin (IL)-6 which in turn stimulate transformation of monocytes to become antigen presenting cells and produce cytokines like IL-1β and IL-23, which further affect T cell function to produce IL-17A. Genetic deletion or neutralization of these cytokines ameliorates hypertension and end-organ damage. In this review, we will consider in depth features of the hypertensive milieu that lead to these events and consider new treatment approaches to limit the untoward effects of inflammation in hypertension.

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Fig. 1: The effect of hypertensive endothelial stretch on monocyte activation.
Fig. 2: The effect of high salt microenvironments on monocyte and dendritic cell activation.
Fig. 3: Potential anti-inflammatory therapies for clinical hypertension.


  1. 1.

    Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease. Circulation. 2019;140:e596–e646.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Harrison DG, Coffman TM, Wilcox CS. Pathophysiology of hypertension. Circ Res. 2021;128:847–863.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Madhur MS, Elijovich F, Alexander MR, Pitzer A, Ishimwe J, Beusecum JPV, et al. Hypertension: do inflammation and immunity hold the key to solving this epidemic? Circ Res. 2021;128:908–933.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, et al. Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunction. J Exp Med. 2007;204:2449–2460.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Norlander AE, Madhur MS, Harrison DG. The immunology of hypertension. J Exp Med. 2018;215:21–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Crowley SD, Song Y-S, Lin EE, Griffiths R, Kim H-S, Ruiz P. Lymphocyte responses exacerbate angiotensin II-dependent hypertension. Am J Physiol Regul Integr Comp Physiol. 2010;298:R1089–R1097.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Mattson DL, Lund H, Guo C, Rudemiller N, Geurts AM, Jacob H. Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage. Am J Physiol Regul Integr Comp Physiol. 2013;304:R407–R414.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Vinh A, Chen W, Blinder Y, Weiss D, Taylor WR, Goronzy JJ, et al. Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension. Circulation. 2010;122:2529–2537.

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Itani HA, Xiao L, Saleh MA, Wu J, Pilkinton MA, Dale BL, et al. CD70 exacerbates blood pressure elevation and renal damage in response to repeated hypertensive stimuli. Circ Res. 2016;118:1233–1243.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Caillon A, Mian MOR, Fraulob-Aquino JC, Huo K-G, Barhoumi T, Ouerd S, et al. γ/δ T cells mediate angiotensin II-induced hypertension and vascular injury. Circulation. 2017;135:2155–2162.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Madhur MS, Lob HE, McCann LA, Iwakura Y, Blinder Y, Guzik TJ, et al. Interleukin 17 promotes angiotensin II–induced hypertension and vascular dysfunction. Hypertension. 2010;55:500–507.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Saleh MA, Norlander AE, Madhur MS. Inhibition of interleukin-17A, but not interleukin-17F, signaling lowers blood pressure, and reduces end-organ inflammation in angiotensin II–induced hypertension. Jacc Basic Transl Sci. 2016;1:606–616.

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Norlander AE, Saleh MA, Kamat NV, Ko B, Gnecco J, Zhu L, et al. Interleukin-17A regulates renal sodium transporters and renal injury in angiotensin II–induced hypertension. Hypertension. 2018;68:167–174.

    Article  CAS  Google Scholar 

  14. 14.

    Nguyen H, Chiasson VL, Chatterjee P, Kopriva SE, Young KJ, Mitchell BM. Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension. Cardiovasc Res. 2013;97:696–704.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Itani HA, Dikalova AE, McMaster WG, Nazarewicz RR, Bikineyeva AT, Harrison DG, et al. Mitochondrial cyclophilin D in vascular oxidative stress and hypertension. Hypertension. 2016;67:1218–1227.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Luther JM, Gainer JV, Murphey LJ, Yu C, Vaughan DE, Morrow JD, et al. Angiotensin II induces interleukin-6 in humans through a mineralocorticoid receptor–dependent mechanism. Hypertension. 2006;48:1050–1057.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Lee DL, Sturgis LC, Labazi H, Osborne JB, Fleming C, Pollock JS, et al. Angiotensin II hypertension is attenuated in interleukin-6 knockout mice. Am J Physiol Heart Circ. 2006;290:H935–H940.

    CAS  Article  Google Scholar 

  18. 18.

    Alexander MR, Norlander AE, Elijovich F, Atreya RV, Gaye A, Gnecco JS, et al. Human monocyte transcriptional profiling identifies IL‐18 receptor accessory protein and lactoferrin as novel immune targets in hypertension. Brit J Pharm. 2019;176:2015–2027.

    CAS  Article  Google Scholar 

  19. 19.

    Landmesser U, Cai H, Dikalov S, McCann L, Hwang J, Jo H, et al. Role of p47phox in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension. 2002;40:511–515.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Wu J, Saleh MA, Kirabo A, Itani HA, Montaniel KRC, Xiao L, et al. Immune activation caused by vascular oxidation promotes fibrosis and hypertension. J Clin Invest. 2016;126:50–67.

    PubMed  Article  Google Scholar 

  21. 21.

    Weber DS, Rocic P, Mellis AM, Laude K, Lyle AN, Harrison DG, et al. Angiotensin II-induced hypertrophy is potentiated in mice overexpressing p22phox in vascular smooth muscle. Am J Physiol-Heart Circ. 2005;288:37–42.

    Article  CAS  Google Scholar 

  22. 22.

    Dikalova A, Clempus R, Lassègue B, Cheng G, McCoy J, Dikalov S, et al. Nox1 overexpression potentiates angiotensin ii-induced hypertension and vascular smooth muscle hypertrophy in transgenic mice. Circulation. 2005;112:2668–2676.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Matsuno K, Yamada H, Iwata K, Jin D, Katsuyama M, Matsuki M, et al. Nox1 is involved in angiotensin II–mediated hypertension. Circulation. 2005;112:2677–2685.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Gavazzi G, Banfi B, Deffert C, Fiette L, Schappi M, Herrmann F, et al. Decreased blood pressure in NOX1‐deficient mice. Febs Lett. 2006;580:497–504.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Mueller CF, Laude K, McNally JS, Harrison DG. ATVB in focus: redox mechanisms in blood vessels. Arteriosclerosis Thrombosis Vasc Biol. 2005;25:274–278.

    CAS  Article  Google Scholar 

  26. 26.

    Kirabo A, Fontana V, Faria APC, de, Loperena R, Galindo CL, Wu J, et al. DC isoketal-modified proteins activate T cells and promote hypertension. J Clin Invest. 2014;124:4642–4656.

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Ciuceis CD, Amiri F, Brassard P, Endemann DH, Touyz RM, Schiffrin EL. Reduced vascular remodeling, endothelial dysfunction, and oxidative stress in resistance arteries of angiotensin II–infused macrophage colony-stimulating factor–deficient mice. Arteriosclerosis Thrombosis Vasc Biol. 2005;25:2106–2113.

    Article  CAS  Google Scholar 

  28. 28.

    Wenzel P, Knorr M, Kossmann S, Stratmann J, Hausding M, Schuhmacher S, et al. Lysozyme M–positive monocytes mediate angiotensin II–induced arterial hypertension and vascular dysfunction. Circulation. 2011;124:1370–1381.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Kossmann S, Hu H, Steven S, Schönfelder T, Fraccarollo D, Mikhed Y, et al. Inflammatory monocytes determine endothelial nitric-oxide synthase uncoupling and nitro-oxidative stress induced by angiotensin II. J Biol Chem. 2014;289:27540–27550.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013;38:792–804.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Randolph GJ, Beaulieu S, Lebecque S, Steinman RM, Muller WA. Differentiation of monocytes into dendritic cells in a model of transendothelial trafficking. Science. 1998;282:480–483.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Loperena R, Beusecum JPV, Itani HA, Engel N, Laroumanie F, Xiao L, et al. Hypertension and increased endothelial mechanical stretch promote monocyte differentiation and activation: roles of STAT3, interleukin 6 and hydrogen peroxide. Cardiovasc Res. 2018;114:1547–1563.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Barbaro NR, Foss JD, Kryshtal DO, Tsyba N, Kumaresan S, Xiao L, et al. Dendritic cell amiloride-sensitive channels mediate sodium-induced inflammation and hypertension. Cell Rep. 2017;21:1009–1020.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Barbaro NR, Beusecum JV, Xiao L, Carmo LD, Pitzer A, Loperena R. et al. Sodium activates human monocytes via the NADPH oxidase and isolevuglandin formation. Cardiovasc Res. 2021;117:1358–1371.

    Article  Google Scholar 

  35. 35.

    Kovarik JJ, Morisawa N, Wild J, Marton A, Takase‐Minegishi K, Minegishi S, et al. Adaptive physiological water conservation explains hypertension and muscle catabolism in experimental chronic renal failure. Acta Physiol. 2021;232:e13629.

    CAS  Article  Google Scholar 

  36. 36.

    Wild J, Jung R, Knopp T, Efentakis P, Benaki D, Grill A, et al. Aestivation motifs explain hypertension and muscle mass loss in mice with psoriatic skin barrier defect. Acta Physiol. 2021;232:e13628.

    CAS  Article  Google Scholar 

  37. 37.

    Beusecum JPV, Barbaro NR, McDowell Z, Aden LA, Xiao L, Pandey AK, et al. High salt activates CD11c+ antigen-presenting cells via SGK (serum glucocorticoid kinase) 1 to promote renal inflammation and salt-sensitive hypertension. Hypertension. 2019;74:555–563.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Fehrenbach DJ, Abais-Battad JM, Dasinger JH, Lund H, Mattson DL. Salt-sensitive increase in macrophages in the kidneys of Dahl SS rats. Am J Physiol Ren. 2019;317:F361–F374.

    CAS  Article  Google Scholar 

  39. 39.

    Tang WHW, Kitai T, Hazen SL. Gut microbiota in cardiovascular health and disease. Circ Res. 2017;120:1183–1196.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Ferguson JF, Aden LA, Barbaro NR, Beusecum JPV, Xiao L, Simmons AJ, et al. High dietary salt-induced dendritic cell activation underlies microbial dysbiosis-associated hypertension. JCI Insight. 2019; 4.

  41. 41.

    Karbach SH, Schönfelder T, Brandão I, Wilms E, Hörmann N, Jäckel S, et al. Gut microbiota promote angiotensin ii–induced arterial hypertension and vascular dysfunction. J Am Heart Assoc. 2016; 5.

  42. 42.

    Pluznick JL, Protzko RJ, Gevorgyan H, Peterlin Z, Sipos A, Han J, et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc Natl Acad Sci USA. 2013;110:4410–4415.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Nakai M, Ribeiro RV, Stevens BR, Gill P, Muralitharan RR, Yiallourou S, et al. Essential hypertension is associated with changes in gut microbial metabolic pathways: a multisite analysis of ambulatory blood pressure. Hypertension. 2021;78:804–815.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Xiao L, Itani HA, Carmo LS, do, Carver LS, Breyer RM, Harrison DG. Central EP3 (E Prostanoid 3) receptors mediate salt-sensitive hypertension and immune activation. Hypertension. 2019;74:1507–1515.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Shah KH, Shi P, Giani JF, Janjulia T, Bernstein EA, Li Y, et al. Myeloid suppressor cells accumulate and regulate blood pressure in hypertension. Circ Res. 2015;117:858–869.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Chiasson VL, Bounds KR, Chatterjee P, Manandhar L, Pakanati AR, Hernandez M, et al. Myeloid-derived suppressor cells ameliorate cyclosporine A–induced hypertension in mice. Hypertension. 2018;71:199–207.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Lu X, Rudemiller NP, Wen Y, Ren J, Hammer GE, Griffiths R, et al. A20 in myeloid cells protects against hypertension by inhibiting dendritic cell-mediated t-cell activation. Circ Res. 2019;125:1055–1066.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Shao B-Z, Xu Z-Q, Han B-Z, Su D-F, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharm. 2015;6:262.

    Article  CAS  Google Scholar 

  49. 49.

    Krishnan SM, Sobey CG, Latz E, Mansell A, Drummond GRIL‐1β. and IL‐18: inflammatory markers or mediators of hypertension? Brit J Pharm. 2014;171:5589–5602.

    CAS  Article  Google Scholar 

  50. 50.

    Dorffel Y, Latsch C, Stuhlmuller B, Schreiber S, Scholze S, Burmester GR, et al. Preactivated peripheral blood monocytes in patients with essential hypertension. Hypertension. 1999;34:113–117.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Omi T, Kumada M, Kamesaki T, Okuda H, Munkhtulga L, Yanagisawa Y, 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. 2006;14:1295–1305.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Krishnan SM, Ling YH, Huuskes BM, Ferens DM, Saini N, Chan CT, et al. Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension. Cardiovasc Res. 2018;115:776–787.

    PubMed Central  Article  CAS  Google Scholar 

  53. 53.

    Ren X-S, Tong Y, Ling L, Chen D, Sun H-J, Zhou H, et al. NLRP3 gene deletion attenuates angiotensin II-induced phenotypic transformation of vascular smooth muscle cells and vascular remodeling. Cell Physiol Biochem. 2018;44:2269–2280.

    Article  CAS  Google Scholar 

  54. 54.

    Bruder-Nascimento T, Ferreira NS, Zanotto CZ, Ramalho F, Pequeno IO, Olivon VC, et al. NLRP3 inflammasome mediates aldosterone-induced vascular damage. Circulation. 2016;134:1866–1880.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Rothman AM, MacFadyen J, Thuren T, Webb A, Harrison DG, Guzik TJ, et al. Effects of interleukin-1β inhibition on blood pressure, incident hypertension, and residual inflammatory risk. Hypertension. 2019;75:477–482.

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Siedlinski M, Jozefczuk E, Xu X, Teumer A, Evangelou E, Schnabel RB, et al. White blood cells and blood pressure: a Mendelian randomization study. Circulation. 2020;141:1307–1317.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Yoshida S, Takeuchi T, Kotani T, Yamamoto N, Hata K, Nagai K, et al. Infliximab, a TNF-α inhibitor, reduces 24-h ambulatory blood pressure in rheumatoid arthritis patients. J Hum Hypertens. 2014;28:165–169.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Herrera J, Ferrebuz A, MacGregor EG, Rodriguez-Iturbe B. Mycophenolate mofetil treatment improves hypertension in patients with psoriasis and rheumatoid arthritis. J Am Soc Nephrol. 2006;17:S218–S225.

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Pitchford LM, Driver PM, Fuller JC, Akers WS, Abumrad NN, Amarnath V, et al. Safety, tolerability, and pharmacokinetics of repeated oral doses of 2-hydroxybenzylamine acetate in healthy volunteers: a double-blind, randomized, placebo-controlled clinical trial. Bmc Pharm Toxicol. 2020;21:3.

    CAS  Article  Google Scholar 

  60. 60.

    Wu J, Thabet SR, Kirabo A, Trott DW, Saleh MA, Xiao L, et al. Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ Res. 2014;114:616–625.

    CAS  PubMed  Article  Google Scholar 

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JVB, HM and DGH composed and edited this review.

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Correspondence to David G. Harrison.

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Van Beusecum, J.P., Moreno, H. & Harrison, D.G. Innate immunity and clinical hypertension. J Hum Hypertens (2021).

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