Abstract
Purpose of Review
To review recent studies exploring how myeloid cell overexpression of angiotensin-converting enzyme (ACE) affects the immune response and to formulate an approach for considering the effectiveness of inflammation in cardiovascular disease
Recent Findings
While it is widely appreciated that the renin-angiotensin system affects aspects of inflammation through the action of angiotensin II, new studies reveal a previously unknown role of ACE in myeloid cell biology. This was apparent from analysis of two mouse lines genetically modified to overexpress ACE in monocytes/macrophages or neutrophils. Cells overexpressing ACE demonstrated an increased immune response. For example, mice with increased macrophage ACE expression have increased resistance to melanoma, methicillin-resistant Staphylococcus aureus, a mouse model of Alzheimer’s disease, and ApoE-knockout-induced atherosclerosis. These data indicate the profound effect of increasing myeloid cell function. Further, they suggest that an appropriate way to evaluate inflammation in both acute and chronic diseases is to ask whether the inflammatory infiltrate is sufficient to eliminate the immune challenge.
Summary
The expression of ACE by myeloid cells induces a heightened immune response by these cells. The overexpression of ACE is associated with immune function beyond that possible by wild type (WT) myeloid cells. A heightened immune response effectively resolves disease in a variety of acute and chronic models of disease including models of Alzheimer’s disease and atherosclerosis.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Zegers RH, Weigl A, Steptoe A. The death of Wolfgang Amadeus Mozart: an epidemiologic perspective. Ann Intern Med. 2009;151:274–8 W96-7.
•• Marchio P, Guerra-Ojeda S, Vila JM, Aldasoro M, Victor VM, Mauricio MD. Targeting early atherosclerosis: a focus on oxidative stress and inflammation. Oxidative Med Cell Longev. 2019;2019:8563845 A good review of the typical paradigm thought to underlie the development of atherosclerosis.
•• Norlander AE, Madhur MS, Harrison DG. The immunology of hypertension. J Exp Med. 2018;215:21–33 An excellent recent review discussing the origins of hypertension and the concept that inflammation plays a major role in its development.
•• Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S24–32 A classic review of many aspects of innate immunity.
• Weiss G, Schaible UE. Macrophage defense mechanisms against intracellular bacteria. Immunol Rev. 2015;264:182–203 An outstanding discussion of the multiple mechanisms macrophages use in defending against tuberculosis.
•• Pamer EG. Immune responses to Listeria monocytogenes. Nat Rev Immunol. 2004;4:812–23 An excellent review of how cytokines are critical for resistance to listeria.
Hirano M. Evolution of vertebrate adaptive immunity: immune cells and tissues, and AID/APOBEC cytidine deaminases. Bioessays. 2015;37:877–87.
Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018;233:6425–40.
Tate MD, Brooks AG, Reading PC, Mintern JD. Neutrophils sustain effective CD8(+) T-cell responses in the respiratory tract following influenza infection. Immunol Cell Biol. 2012 Feb;90(2):197–205.
Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. Int J Biochem Cell Biol. 2003;35:881–900.
Schiffrin EL. Vascular and cardiac benefits of angiotensin receptor blockers. Am J Med. 2002;113:409–18.
Mann DL. Angiotensin II as an inflammatory mediator: evolving concepts in the role of the renin angiotensin system in the failing heart. Cardiovasc Drugs Ther. 2002;16:7–9.
Marchesi C, Paradis P, Schiffrin EL. Role of the renin-angiotensin system in vascular inflammation. Trends Pharmacol Sci. 2008;29:367–74.
Montecucco F, Pende A, Mach F. The renin-angiotensin system modulates inflammatory processes in atherosclerosis: evidence from basic research and clinical studies. Mediat Inflamm. 2009;2009:752406.
Alvarez A, Cerdá-Nicolás M, Naim Abu Nabah Y, Mata M, Issekutz AC, Panés J, et al. Direct evidence of leukocyte adhesion in arterioles by angiotensin II. Blood. 2004;104:402–8.
Han C, Liu J, Liu X, Li M. Angiotensin II induces C-reactive protein expression through ERK1/2 and JNK signaling in human aortic endothelial cells. Atherosclerosis. 212:206–12.
Piqueras L, Kubes P, Alvarez A, O’Connor E, Issekutz AC, Esplugues JV, et al. Angiotensin II induces leukocyte-endothelial cell interactions in vivo via AT(1) and AT(2) receptor-mediated P-selectin upregulation. Circulation. 2000;102:2118–23.
•• Bernstein KE, Ong FS, Blackwell W-LB, Shah KH, Giani JF, Gonzalez-Villalobos RA, et al. A modern understanding of the traditional and non-traditional biological functions of angiotensin converting enzyme (ACE). Pharmacol Rev. 2013;65:1–46 A complete review of the biology of ACE.
• Semis M, Gugiu GB, Bernstein EA, Bernstein KE, Kalkum M. The plethora of angiotensin-converting enzyme substrates in mouse plasma. Anal Chem. 2019;91:6440–53 Analysis by mass spectrometry of peptides produced by ACE.
Soubrier F, Alhenc-Gelas F, Hubert C, Allegrini J, John M, Tregear G, et al. Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. Proc Natl Acad Sci U S A. 1988;85:9386–90.
Bernstein KE, Martin BM, Edwards AS, Bernstein EA. Mouse angiotensin-converting enzyme is a protein composed of two homologous domains. J Biol Chem. 1989;264:11945–51.
• Wei L, Alhenc-Gelas F, Corvol P, Clauser E. The two homologous domains of human angiotensin I-converting enzyme are both catalytically active. J Biol Chem. 1991;266:9002–8 An outstanding paper proving that ACE has two independent catalytic domains.
• Hagaman JR, Moyer JS, Bachman ES, Sibony M, Magyar PL, Welch JE, et al. Angiotensin-converting enzyme and male fertility. Proc Natl Acad Sci U S A. 1998;95:2552–7 An excellent paper of the role of testis ACE in reproduction.
• Lieberman J. Elevation of serum angiotensin-converting-enzyme (ACE) level in sarcoidosis. Am J Med. 1975;59:365–72 An outstanding example of how a clinical observation can lead (eventually) to basic insights.
Baudin B. New aspects on angiotensin-converting enzyme: from gene to disease. Clin Chem Lab Med. 2002;40:256–65.
Williams GT, Williams WJ. Granulomatous inflammation - a review. J Clin Pathol. 1983;36:723–33.
Brice EA, Friedlander W, Bateman ED, Kirsch RE. Serum angiotensin-converting enzyme activity, concentration, and specific activity in granulomatous interstitial lung disease, tuberculosis, and COPD. Chest. 1995;107:706–10.
Bernstein KE, Khan Z, Giani JF, Cao DY, Bernstein EA, Shen XZ. Angiotensin-converting enzyme in innate and adaptive immunity. Nat Rev Nephrol. 2018;14:325–36.
Cronan MR, Beerman RW, Rosenberg AF, Saelens JW, Johnson MG, Oehlers SH, et al. Macrophage epithelial reprogramming underlies mycobacterial granuloma formation and promotes infection. Immunity. 2016;45:861–76.
• Diet F, Pratt RE, Berry GJ, Momose N, Gibbons GH, Dzau VJ. Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation. 1996;94:2756–67 A classic paper showing that macrophages found in all stages of atherosclerosis make abundant ACE.
Ohishi M, Ueda M, Rakugi H, Naruko T, Kojima A, Okamura A, et al. Enhanced expression of angiotensin-converting enzyme is associated with progression of coronary atherosclerosis in humans. J Hypertens. 1997;15:1295–302.
Danilov SM, Tikhomirova VE, Metzger R, Naperova IA, Bukina TM, Goker-Alpan O, et al. ACE phenotyping in Gaucher disease. Mol Genet Metab. 2018;123:501–10.
•• Khan Z, Shen XZ, Bernstein EA, Giani JF, Eriguchi M, Zhao TV, et al. Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils. Blood. 2017;130:328–39 A very comprehensive analysis of the role of ACE in neutrophil function.
Shen XZ, Billet S, Lin C, Okwan-Duodu D, Chen X, Lukacher AE, et al. The carboxypeptidase ACE shapes the MHC class I peptide repertoire. Nat Immunol. 2011;12:1078–85.
• Shen XZ, Li P, Weiss D, Fuchs S, Xiao HD, Adams JA, et al. Mice with enhanced macrophage angiotensin-converting enzyme are resistant to melanoma. Am J Pathol. 2007;170:2122–34 This is the first study to memorialize the observation that ACE overexpression induces an increase of macrophage immune response.
Okwan-Duodu D, Datta V, Shen XZ, Goodridge HS, Bernstein EA, Fuchs S, et al. Angiotensin-converting enzyme overexpression in mouse myelomonocytic cells augments resistance to Listeria and methicillin-resistant Staphylococcus aureus. J Biol Chem. 2010;285:39051–60.
•• Bernstein KE, Koronyo Y, Salumbides BC, Sheyn J, Pelissier L, Lopes DH, et al. Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline. J Clin Invest. 2014;124:1000–12 Demonstration that an increased immune response can greatly affect the pathology of a mouse model of AD.
• Okwan-Duodu D, Weiss D, Peng Z, Veiras LC, Cao DY, Saito S, et al. Overexpression of myeloid angiotensin-converting enzyme (ACE) reduces atherosclerosis. Biochem Biophys Res Commun. 2019;S0006-291X(19):31971–0. Mice over expressing ACE in macrophages (ACE 10/10 mice) have reduced atherosclerosis as compared to WT mice.
• Ridker PM, Libby P, JG MF, Thuren T, Ballantyne C, Fonseca F, et al. Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J. 2018;39:3499–507 Outstanding study investigating the role of inflammation in atherosclerosis pathology.
Schieffer B, Selle T, Hilfiker A, Hilfiker-Kleiner D, Grote K, Tietge UJ, et al. Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis. Circulation. 2004;110:3493–500.
Luchtefeld M, Schunkert H, Stoll M, Selle T, Lorier R, Grote K, et al. Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man. J Exp Med. 2007;204:1935–44.
Davenport P, Tipping PG. The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein e-deficient mice. Am J Pathol. 2003;163:1117–25.
George J, Mulkins M, Shaish A, Casey S, Schatzman R, Sigal E, et al. Interleukin (IL)-4 deficiency does not influence fatty streak formation in C57BL/6 mice. Atherosclerosis. 2000;153:403–11.
Wang J, Sun C, Gerdes N, Liu C, Liao M, Liu J, et al. Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter. Nat Med. 2015;21:820–6.
Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114:1852–66.
Kim K, Shim D, Lee JS, Zaitsev K, Williams JW, Kim KW, Jang MY, Seok Jang H, Yun TJ, Lee SH, Yoon WK, Prat A, Seidah NG, Choi J, Lee SP, Yoon SH, Nam JW, Seong JK, Oh GT, Randolph GJ, Artyomov MN, Cheong C, Choi JH. Circ Res 2018; 123:1127–1142.
Funding
This work was supported by National Institutes of Health Grants P01HL129941 (K.E.B.), R01AI143599 (K.E.B.), R01HL142672 (J.F.G.), R01AG055865 (M.K.H.), T32DK007770 (L.C.V.), K99HL141638 (DOD), P30DK063491 (J.F.G.), and the American Heart Association (AHA) Grants 17GRNT33661206 (K.E.B.), 16SDG30130015 (J.F.G.), and 19CDA34760010 (Z.K.). M.K.H. is supported by BrightFocus Foundation Award A2013328S00.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare no conflicts of interest relevant to this manuscript.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Inflammation and Cardiovascular Diseases
Rights and permissions
About this article
Cite this article
Veiras, L.C., Cao, D., Saito, S. et al. Overexpression of ACE in Myeloid Cells Increases Immune Effectiveness and Leads to a New Way of Considering Inflammation in Acute and Chronic Diseases. Curr Hypertens Rep 22, 4 (2020). https://doi.org/10.1007/s11906-019-1008-x
Published:
DOI: https://doi.org/10.1007/s11906-019-1008-x