Immune system and Arterial Hypertension: History
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Subjects: Pathology
Contributor:
Patricio Araos
,
Stefanny Figueroa
,
Cristián A. Amador

It is well-accepted that immune system and some cells from adaptive and innate immunity are necessary for the initiation/perpetuation of arterial hypertension (AH). However, whether neutrophils are part of this group remains debatable. There are evidences showing that neutrophil/lymphocyte ratio correlates with AH and is higher in non-dipper patients. On the other hand, the experimental neutrophil depletion in mice reduces basal blood pressure, nevertheless, their participation in AH is still controversial. Apparently, neutrophils may modulate the microenvironment in blood vessels by increasing oxidative stress favor the endothelial disfunction. In addition, neutrophils may contribute to the tissue infiltration of immune cells, secreting chemoattractant chemokines/cytokines and promoting the pro-inflammatory phenotype driving to the AH development. In this work, we discuss the potential role of neutrophils in AH by analyzing different mechanisms proposed from clinical and basic studies, with a perspective upon cardiovascular and renal damages relating to the hypertensive phenotype.

  • Arterial Hypertension
  • Immune System
  • Kidney Disease
  • Cardiovascular Risk
  • neutrophils

1. Introduction

Arterial hypertension (AH) is a worldwide health problem and a huge economic burden in developing and developed nations, where the projected cost for 2030 in the United States of America (USA), for example, could reach values upward of USD 200 billion[1]. AH affects 31.1% of the population[2] and its inappropriate handling represents the leading risk factor for mortality worldwide[3][4]. In this sense, AH can promote chronic kidney disease, another critical cardiovascular (CV) risk factor, affecting ~13% of the population, and this remains one of the leading causes for progression to end-stage renal disease requiring renal replacement therapies. Therefore, AH, renal, and CV diseases are complex conditions with a demonstrated causal relationship, supporting the need of new alternatives for earlier detection and adequate treatment.

Above 70% of AH patients have no etiology and they remain categorized as “essential” or “primary”. The origin of this situation is complex and multifactorial, and it involves the interaction of several physiological systems boosted by exposure to lifestyle risk factors[2].

2. Role of Immune System in Hypertension

The evidence linking the immune system and AH dates from the 1960s[5][6]; however, the hypothesis of a causal role of the immune system in AH was proposed years later by Okuda and Grollman, where the transference of lymph node cells from rats with unilateral renal artery ligation induced AH in recipient rats[7]. Likewise, splenocytes from rats treated with deoxycorticosterone acetate (DOCA) salt induced AH in normotensive animals[8]. Conversely, the absence of thymus was sufficient to protect against AH development in the DOCA salt and genetic models[9][10], while thymus grafting from wild-type mice (WT) into nude mice (resistant to AH generation) restored their sensitivity to DOCA salt-dependent AH[9]. In this context, the most recent evidence suggests that the autonomic nervous system may control the immune system[11], since there is a neuroimmune boost at the splenic level during AH[12]. This emerging evidence proposes the autonomic nervous system as a modulator of the immune system in AH, beyond its classic effects on heart rate, vascular tone, and sodium excretion.

Guzik et al. found that T lymphocytes and not B lymphocytes were necessary for AH development and vascular dysfunction, as a result of DOCA salt or angiotensin II (AngII)[13]. Years later, these findings were confirmed by other groups and in other experimental settings of AH that included salt sensitivity[14][15]. In addition, it was suggested that T lymphocytes can be activated by a cholinergic impulse, through a vagus nerve connection to the spleen, promoting their migration to the target organs and contributing to AH[12].

In the last 10 years, different lymphocytes have been studied in order to establish their role in blood pressure control. On the adaptive immunity side, CD8+ T cells apparently participate in AH by increasing renal sodium reabsorption through the activation of specific transporters[16][17]. On the other hand, CD4+ lymphocytes, both T helper 1 (TH1) cells and TH17 cells, accumulate in the vessels, spleen, and kidney during AH[18][19]. Causal involvement of CD4+ cells was demonstrated by blood pressure modulation in various studies using genetically lacking CD4+ lymphocytes animals or knockout (KO) animals for cytokines from TH1 or TH17 cells[20][21][22]. However, since other cells can also secrete these cytokines, the involvement of TH1 and TH17 has not been entirely clarified. Contrarily, it has been proposed that the activity of regulatory T (Treg) cells, a subpopulation of CD4+ lymphocytes, could be decreased in AH. Different studies have shown a decreasing Treg cell population in plasma, spleen, or kidney during AH, while the selective depletion of Treg cells raises blood pressure and exacerbates target organ damage in experimental models[23][24]. In all these studies, the adoptive transfer (or activation) of Treg cells prevented AH and CV damage in response to AngII or aldosterone, supporting their promissory use in cell therapy strategies.

Regarding the innate immune cells, unconventional γδ T cells that present a rapid innate-like response initiating immune response are involved in AH development by regulating vasoconstriction and by secreting large amounts of interleukin (IL)-17[25]. These observations delineated new perspectives for IL-17, beyond TH17 lymphocytes. On the other hand, dendritic cells (DCs) are considered as critical for the AH since there is evidence showing that they participate in TH1 and TH17 cell activation, by taking up neoantigens and through isoketal formation after Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation[26][27]. Moreover, van Beusecum et al. demonstrated that the specific deletion of serum glucocorticoid kinase 1 (SGK1) in DCs prevents AH, vascular dysfunction, and kidney inflammation induced by N-Nitro-l-arginine methyl ester (L-NAME) plus a high-salt diet[28]. Apparently, SGK1 may function as a sodium sensor, allowing DC activation; this effect was also observed in CD4+ lymphocytes[29]. The orchestrated responses by DCs are supported by a recent study showing that the absence of DCs protects against renal dysfunction, kidney damage, and CV inflammation/fibrosis in an AngII-dependent hypertensive model[30]. The protective effect of DC depletion for AH development was also corroborated in the nephrectomy aldosterone salt (NAS) model, which involved the prevention of cardiac hypertrophy and fibrosis[31]. Finally, monocytes and macrophages have also been implicated, principally due to their increase and the phenotypic changes in vasculature, kidney, heart, and brain during AH[32], promoting fibrosis and maintaining AH through NADPH oxidase-dependent mechanisms in vascular tissue[33][34]. In general, the accumulative evidence suggests that innate and adaptive immunity are involved in the pathophysiology of AH and in associated end-organ damage. However, the specific immune cells that promote AH and tissue damage are still under study, where the role of neutrophils remains to be addressed.

This entry is adapted from the peer-reviewed paper 10.3390/ijms21228536

References

  1. Heidenreich, P.A.; Trogdon, J.G.; Khavjou, O.A.; Butler, J.; Dracup, K.; Ezekowitz, M.D.; Finkelstein, E.A.; Hong, Y.; Johnston, S.C.; Khera, A.; et al. Forecasting the future of cardiovascular disease in the United States: A policy statement from the American Heart Association. Circulation 2011, 123, 933–944.
  2. Mills, K.T.; Bundy, J.D.; Kelly, T.N.; Reed, J.E.; Kearney, P.M.; Reynolds, K.; Chen, J.; He, J. Global Disparities of Hypertension Prevalence and Control: A Systematic Analysis of Population-Based Studies From 90 Countries. Circulation 2016, 134, 441–450.
  3. 2017 Risk Factor Collaborators. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392, 1923–1994.
  4. Collaborators, G.B.D.C.o.D. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392, 1736–1788.
  5. Koroskenyi, K.; Juba, F.; Vajda, G. Human vascular antigen complement consumption test of hypertensive patients (preliminary report). Experientia 1961, 17, 91–92.
  6. Hilme, E.; Herlitz, H.; Soderstrom, T.; Hansson, L. Increased secretion of immunoglobulins in malignant hypertension. J. Hypertens. 1989, 7, 91–95.
  7. Okuda, T.; Grollman, A. Passive transfer of autoimmune induced hypertension in the rat by lymph node cells. Tex. Rep. Biol. Med. 1967, 25, 257–264.
  8. Olsen, F. Transfer of arterial hypertension by splenic cells from DOCA-salt hypertensive and renal hypertensive rats to normotensive recipients. Acta Pathol. Microbiol. Scand. C 1980, 88, 1–5.
  9. Svendsen, U.G. Evidence for an initial, thymus independent and a chronic, thymus dependent phase of DOCA and salt hypertension in mice. Acta Pathol. Microbiol. Scand. A 1976, 84, 523–528.
  10. A Bataillard; J C Freiche; M Vincent; J Sassard; J L Touraine; Antihypertensive effect of neonatal thymectomy in the genetically hypertensive LH rat.. Thymus 1986, 8, 321–330, .
  11. M. J. Kenney; C. K. Ganta; Autonomic Nervous System and Immune System Interactions. Comprehensive Physiology 2014, 4, 1177-1200, 10.1002/cphy.c130051.
  12. Daniela Carnevale; Marialuisa Perrotta; Fabio Pallante; Valentina Fardella; Roberta Iacobucci; Stefania Fardella; Lorenzo Carnevale; Raimondo Carnevale; Massimiliano De Lucia; Giuseppe Cifelli; et al. A cholinergic-sympathetic pathway primes immunity in hypertension and mediates brain-to-spleen communication. Nature Communications 2016, 7, 13035, 10.1038/ncomms13035.
  13. Tomasz J. Guzik; Nyssa E. Hoch; Kathryn A. Brown; Louise A. McCann; Ayaz Rahman; Sergey Dikalov; Jorg Goronzy; Cornelia Weyand; David G. Harrison; Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunction. Journal of Experimental Medicine 2007, 204, 2449-2460, 10.1084/jem.20070657.
  14. Fehrenbach, D.J.; Dasinger, J.H.; Lund, H.; Zemaj, J.; Mattson, D.L. Splenocyte transfer exacerbates salt-sensitive hypertension in rats. Exp. Physiol. 2020, 105, 864–875.
  15. Crowley, S.D.; Song, Y.S.; Lin, E.E.; 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.
  16. Trott, D.W.; Thabet, S.R.; Kirabo, A.; Saleh, M.A.; Itani, H.; Norlander, A.E.; Wu, J.; Goldstein, A.; Arendshorst, W.J.; Madhur, M.S.; et al. Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Hypertension 2014, 64, 1108–1115.
  17. Liu, Y.; Rafferty, T.M.; Rhee, S.W.; Webber, J.S.; Song, L.; Ko, B.; Hoover, R.S.; He, B.; Mu, S. CD8(+) T cells stimulate Na-Cl co-transporter NCC in distal convoluted tubules leading to salt-sensitive hypertension. Nat. Commun. 2017, 8, 14037.
  18. Itani, H.A.; McMaster, W.G., Jr.; Saleh, M.A.; Nazarewicz, R.R.; Mikolajczyk, T.P.; Kaszuba, A.M.; Konior, A.; Prejbisz, A.; Januszewicz, A.; Norlander, A.E.; et al. Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans. Hypertension 2016, 68, 123–132.
  19. Ji, Q.; Cheng, G.; Ma, N.; Huang, Y.; Lin, Y.; Zhou, Q.; Que, B.; Dong, J.; Zhou, Y.; Nie, S. Circulating Th1, Th2, and Th17 Levels in Hypertensive Patients. Dis. Markers 2017, 2017, 7146290.
  20. Norlander, A.E.; Madhur, M.S. Inflammatory cytokines regulate renal sodium transporters: How, where, and why? Am. J. Physiol. Ren. Physiol. 2017, 313, F141–F144.
  21. Kamat, N.V.; Thabet, S.R.; Xiao, L.; Saleh, M.A.; Kirabo, A.; Madhur, M.S.; Delpire, E.; Harrison, D.G.; McDonough, A.A. Renal transporter activation during angiotensin-II hypertension is blunted in interferon-γ-/- and interleukin-17A-/- mice. Hypertension 2015, 65, 569–576.
  22. Amador, C.A.; Barrientos, V.; Peña, J.; Herrada, A.A.; González, M.; Valdés, S.; Carrasco, L.; Alzamora, R.; Figueroa, F.; Kalergis, A.M.; et al. Spironolactone decreases DOCA-salt-induced organ damage by blocking the activation of T helper 17 and the downregulation of regulatory T lymphocytes. Hypertension 2014, 63, 797–803.
  23. Kasal, D.A.; Barhoumi, T.; Li, M.W.; Yamamoto, N.; Zdanovich, E.; Rehman, A.; Neves, M.F.; Laurant, P.; Paradis, P.; Schiffrin, E.L. T regulatory lymphocytes prevent aldosterone-induced vascular injury. Hypertension 2012, 59, 324–330.
  24. Katsuki, M.; Hirooka, Y.; Kishi, T.; Sunagawa, K. Decreased proportion of Foxp3+ CD4+ regulatory T cells contributes to the development of hypertension in genetically hypertensive rats. J. Hypertens. 2015, 33, 773–783, discussion 783.
  25. Antoine Caillon; Muhammad Oneeb Rehman Mian; Julio C. Fraulob-Aquino; Ku-Geng Huo; Tlili Barhoumi; Sofiane Ouerd; Peter R. Sinnaeve; Pierre Paradis; Ernesto L. Schiffrin; γδ T Cells Mediate Angiotensin II-Induced Hypertension and Vascular Injury. Circulation 2017, 135, 2155-2162, 10.1161/circulationaha.116.027058.
  26. Kirabo, A.; Fontana, V.; de Faria, A.P.; Loperena, R.; Galindo, C.L.; Wu, J.; Bikineyeva, A.T.; Dikalov, S.; Xiao, L.; Chen, W.; et al. DC isoketal-modified proteins activate T cells and promote hypertension. J. Clin. Investig. 2014, 124, 4642–4656.
  27. Barbaro, N.R.; Foss, J.D.; Kryshtal, D.O.; Tsyba, N.; Kumaresan, S.; Xiao, L.; Mernaugh, R.L.; Itani, H.A.; Loperena, R.; Chen, W.; et al. Dendritic Cell Amiloride-Sensitive Channels Mediate Sodium-Induced Inflammation and Hypertension. Cell Rep. 2017, 21, 1009–1020.
  28. Justin P. Van Beusecum; Natalia R. Barbaro; Zoe McDowell; Luul A. Aden; Liang Xiao; Arvind K. Pandey; Hana A. Itani; Lauren E. Himmel; David G. Harrison; Annet Kirabo; 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, 10.1161/hypertensionaha.119.12761.
  29. Allison E. Norlander; Mohamed A. Saleh; Arvind K. Pandey; Hana A. Itani; Jing Wu; Liang Xiao; Jooeun Kang; Bethany L. Dale; Slavina B. Goleva; Fanny Laroumanie; et al. A salt-sensing kinase in T lymphocytes, SGK1, drives hypertension and hypertensive end-organ damage. JCI Insight 2017, 2, null, 10.1172/jci.insight.92801.
  30. Daniel Hevia; Patricio Araos; Carolina Prado; Eugenia Fuentes Luppichini; Macarena Rojas; Rodrigo Alzamora; Flavia Cifuentes-Araneda; Alexis A. Gonzalez; Cristian A. Amador; Rodrigo Pacheco; et al. Myeloid CD11c + Antigen-Presenting Cells Ablation Prevents Hypertension in Response to Angiotensin II Plus High-Salt Diet. Hypertension 2018, 71, 709-718, 10.1161/hypertensionaha.117.10145.
  31. Patricio Araos; Carolina Prado; Mauricio Lozano; Stefanny Figueroa; Alexandra Espinoza; Thorsten Berger; Tak W. Mak; Frédéric Jaisser; Rodrigo Pacheco; Luis Michea; et al. Dendritic cells are crucial for cardiovascular remodeling and modulate neutrophil gelatinase-associated lipocalin expression upon mineralocorticoid receptor activation. Journal of Hypertension 2019, 37, 1482-1492, 10.1097/hjh.0000000000002067.
  32. A. Justin Rucker; Steven D. Crowley; The role of macrophages in hypertension and its complications. Pflügers Archiv - European Journal of Physiology 2017, 469, 419-430, 10.1007/s00424-017-1950-x.
  33. Wenzel, P.; Knorr, M.; Kossmann, S.; Stratmann, J.; Hausding, M.; Schuhmacher, S.; Karbach, S.H.; Schwenk, M.; Yogev, N.; Schulz, E.; et al. Lysozyme M-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction. Circulation 2011, 124, 1370–1381.
  34. Sag, C.M.; Schnelle, M.; Zhang, J.; Murdoch, C.E.; Kossmann, S.; Protti, A.; Santos, C.X.C.; Sawyer, G.; Zhang, X.; Mongue-Din, H.; et al. Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure. Circulation 2017, 135, 2163–2177.
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