Abstract
Cardiometabolic disorders were originally thought to be driven primarily by changes in lipid metabolism that cause the accumulation of lipids in organs, thereby impairing their function. Thus, in the setting of cardiovascular disease, statins — a class of lipid-lowering drugs — have remained the frontline therapy. In the past 20 years, seminal discoveries have revealed a central role of both the innate and adaptive immune system in driving cardiometabolic disorders. As such, it is now appreciated that immune-based interventions may have an important role in reducing death and disability from cardiometabolic disorders. However, to date, there have been a limited number of clinical trials exploring this interventional strategy. Nonetheless, elegant preclinical research suggests that immune-targeted therapies can have a major impact in treating cardiometabolic disease. Here, we discuss the history and recent advancements in the use of immunotherapies to treat cardiometabolic disorders.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout


Similar content being viewed by others
References
Ross, R. Atherosclerosis–an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).
Pearson, T. A. et al. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation 106, 388–391 (2002).
Greenland, P. et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 122, e584–e636 (2010).
Arnett, D. K. et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 140, e596–e646 (2019).
Wolf, D. & Ley, K. Immunity and inflammation in atherosclerosis. Circ. Res. 124, 315–327 (2019).
Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).
Kubota, T. et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ. Res. 81, 627–635 (1997).
Aikawa, R. et al. Reactive oxygen species in mechanical stress-induced cardiac hypertrophy. Biochem. Biophys. Res. Commun. 289, 901–907 (2001).
Bradham, W. S., Bozkurt, B., Gunasinghe, H., Mann, D. & Spinale, F. G. Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective. Cardiovasc. Res. 53, 822–830 (2002).
Bozkurt, B. et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation 103, 1044–1047 (2001).
Chung, E. S. et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 107, 3133–3140 (2003).
Esser, N., Paquot, N. & Scheen, A. J. Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease. Expert Opin. Investig. Drugs 24, 283–307 (2015).
Bernstein, L. E., Berry, J., Kim, S., Canavan, B. & Grinspoon, S. K. Effects of etanercept in patients with the metabolic syndrome. Arch. Intern. Med. 166, 902–908 (2006).
Branen, L. et al. Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice. Arterioscler. Thromb. Vasc. Biol. 24, 2137–2142 (2004).
Xanthoulea, S. et al. Absence of p55 TNF receptor reduces atherosclerosis, but has no major effect on angiotensin II induced aneurysms in LDL receptor deficient mice. PLoS One 4, e6113 (2009).
Dinarello, C. A., Renfer, L. & Wolff, S. M. Human leukocytic pyrogen: purification and development of a radioimmunoassay. Proc. Natl Acad. Sci. USA 74, 4624–4627 (1977).
Shimokawa, H. et al. Chronic treatment with interleukin-1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derived growth factor. J. Clin. Invest. 97, 769–776 (1996).
Kirii, H. et al. Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 23, 656–660 (2003).
Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).
Ridker, P. M. et al. Low-dose methotrexate for the prevention of atherosclerotic events. N. Engl. J. Med. 380, 752–762 (2019).
Nidorf, S. M. et al. Colchicine in patients with chronic coronary disease. N. Engl. J. Med. 383, 1838–1847 (2020).
Tardif, J. C. et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N. Engl. J. Med. 381, 2497–2505 (2019).
Kurup, R., Galougahi, K. K., Figtree, G., Misra, A. & Patel, S. The role of colchicine in atherosclerotic cardiovascular disease. Heart Lung Circ. 30, 795–806 (2021).
McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).
Williams, J. W., Huang, L. H. & Randolph, G. J. Cytokine circuits in cardiovascular disease. Immunity 50, 941–954 (2019).
Choy, E., Ganeshalingam, K., Semb, A. G., Szekanecz, Z. & Nurmohamed, M. Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment. Rheumatology 53, 2143–2154 (2014).
Kraakman, M. J., Dragoljevic, D., Kammoun, H. L. & Murphy, A. J. Is the risk of cardiovascular disease altered with anti-inflammatory therapies? Insights from rheumatoid arthritis. Clin. Transl Immunol. 5, e84 (2016).
Rajavashisth, T. et al. Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor- deficient mice. J. Clin. Invest. 101, 2702–2710 (1998).
Barnabe, C., Martin, B. J. & Ghali, W. A. Systematic review and meta-analysis: anti-tumor necrosis factor alpha therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res. 63, 522–529 (2011).
Cholesterol Treatment Trialists Collaboration. et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 376, 1670–1681 (2010).
Nissen, S. E. et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N. Engl. J. Med. 352, 29–38 (2005).
Oesterle, A., Laufs, U. & Liao, J. K. Pleiotropic effects of statins on the cardiovascular system. Circ. Res. 120, 229–243 (2017).
Musunuru, K. et al. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature 593, 429–434 (2021).
Rothgangl, T. et al. In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels. Nat. Biotechnol. https://doi.org/10.1038/s41587-021-00933-4 (2021).
Gaudelli, N. M. et al. Programmable base editing of A*T to G*C in genomic DNA without DNA cleavage. Nature 551, 464–471 (2017).
Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016).
Yeh, W. H., Chiang, H., Rees, H. A., Edge, A. S. B. & Liu, D. R. In vivo base editing of post-mitotic sensory cells. Nat. Commun. 9, 2184 (2018).
Charlesworth, C. T. et al. Identification of preexisting adaptive immunity to Cas9 proteins in humans. Nat. Med. 25, 249–254 (2019).
Li, A. et al. AAV-CRISPR gene editing is negated by pre-existing immunity to Cas9. Mol. Ther. 28, 1432–1441 (2020).
Momtazi-Borojeni, A. A. et al. PCSK9 and inflammation: a review of experimental and clinical evidence. Eur. Heart J. Cardiovasc. Pharmacother. 5, 237–245 (2019).
Pradhan, A. D., Aday, A. W., Rose, L. M. & Ridker, P. M. Residual inflammatory risk on treatment with PCSK9 inhibition and statin therapy. Circulation 138, 141–149 (2018).
Linsel-Nitschke, P. & Tall, A. R. HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nat. Rev. Drug Discov. 4, 193–205 (2005).
Tall, A. R. & Rader, D. J. Trials and tribulations of CETP inhibitors. Circ. Res. 122, 106–112 (2018).
Fotakis, P. et al. Anti-inflammatory effects of HDL (high-density lipoprotein) in macrophages predominate over proinflammatory effects in atherosclerotic plaques. Arterioscler. Thromb. Vasc. Biol. 39, e253–e272 (2019).
Suzuki, M. et al. High-density lipoprotein suppresses the type I interferon response, a family of potent antiviral immunoregulators, in macrophages challenged with lipopolysaccharide. Circulation 122, 1919–1927 (2010).
Nissen, S. E. et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 290, 2292–2300 (2003).
Tardif, J. C. et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 297, 1675–1682 (2007).
Shaw, J. A. et al. Infusion of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque. Circ. Res. 103, 1084–1091 (2008).
Nicholls, S. J. et al. Relationship between atheroma regression and change in lumen size after infusion of apolipoprotein A-I Milano. J. Am. Coll. Cardiol. 47, 992–997 (2006).
Murphy, A. J. et al. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J. Clin. Invest. 121, 4138–4149 (2011).
Murphy, A. J. et al. Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis. Nat. Med. 19, 586–594 (2013).
Murphy, A. J. et al. High-density lipoprotein reduces the human monocyte inflammatory response. Arterioscler. Thromb. Vasc. Biol. 28, 2071–2077 (2008).
Murphy, A. J. et al. Neutrophil activation is attenuated by high-density lipoprotein and apolipoprotein A-I in in vitro and in vivo models of inflammation. Arterioscler. Thromb. Vasc. Biol. 31, 1333–1341 (2011).
Patel, S. et al. Reconstituted high-density lipoprotein increases plasma high-density lipoprotein anti-inflammatory properties and cholesterol efflux capacity in patients with type 2 diabetes. J. Am. Coll. Cardiol. 53, 962–971 (2009).
Nicholls, S. J. et al. Reconstituted high-density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits. Circulation 111, 1543–1550 (2005).
Catapano, A. L., Pirillo, A., Bonacina, F. & Norata, G. D. HDL in innate and adaptive immunity. Cardiovasc. Res. 103, 372–383 (2014).
Westerterp, M. et al. Cholesterol accumulation in dendritic cells links the inflammasome to acquired immunity. Cell Metab. 25, 1294–1304.e6 (2017).
Dragoljevic, D. et al. Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis. Eur. Heart J. 39, 2158–2167 (2018).
Rayner, K. J. et al. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J. Clin. Invest. 121, 2921–2931 (2011).
Rayner, K. J. et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328, 1570–1573 (2010).
Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).
van der Heijden, T. et al. NLRP3 inflammasome inhibition by MCC950 reduces atherosclerotic lesion development in apolipoprotein E-deficient mice-brief report. Arterioscler. Thromb. Vasc. Biol. 37, 1457–1461 (2017).
Menu, P. et al. Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome. Cell Death Dis. 2, e137 (2011).
Westerterp, M. et al. Cholesterol efflux pathways suppress inflammasome activation, NETosis, and atherogenesis. Circulation 138, 898–912 (2018).
Sharma, A. et al. Specific NLRP3 inhibition protects against diabetes-associated atherosclerosis. Diabetes 70, 772–787 (2021).
Dinarello, C. A. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27, 519–550 (2009).
Sreejit, G. et al. Neutrophil-derived S100A8/A9 amplify granulopoiesis after myocardial infarction. Circulation 141, 1080–1094 (2020).
Nagareddy, P. R. et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 19, 821–835 (2014).
Kraakman, M. J. et al. Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metab. 21, 403–416 (2015).
Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).
Kammoun, H. L. et al. Evidence against a role for NLRP3-driven islet inflammation in db/db mice. Mol. Metab. 10, 66–73 (2018).
Bick, A. G. et al. Genetic interleukin 6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis. Circulation 141, 124–131 (2020).
Fidler, T. P. et al. The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis. Nature 592, 296–301 (2021).
Fuster, J. J. et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842–847 (2017).
Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111–121 (2017).
Sano, S. et al. CRISPR-mediated gene editing to assess the roles of Tet2 and Dnmt3a in clonal hematopoiesis and cardiovascular disease. Circ. Res. 123, 335–341 (2018).
Swirski, F. K. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J. Clin. Invest. 117, 195–205 (2007).
Yvan-Charvet, L. et al. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 328, 1689–1693 (2010).
Wang, M. et al. Interleukin-3/granulocyte macrophage colony-stimulating factor receptor promotes stem cell expansion, monocytosis, and atheroma macrophage burden in mice with hematopoietic ApoE deficiency. Arterioscler. Thromb. Vasc. Biol. 34, 976–984 (2014).
Kim, S. et al. Angiotensin II regulation of proliferation, differentiation, and engraftment of hematopoietic stem cells. Hypertension 67, 574–584 (2016).
Al-Sharea, A. et al. Chronic sympathetic driven hypertension promotes atherosclerosis by enhancing hematopoiesis. Haematologica 104, 456–467 (2019).
Daugherty, A., Manning, M. W. & Cassis, L. A. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J. Clin. Invest. 105, 1605–1612 (2000).
Drummond, G. R., Vinh, A., Guzik, T. J. & Sobey, C. G. Immune mechanisms of hypertension. Nat. Rev. Immunol. 19, 517–532 (2019).
Nagareddy, P. R. et al. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 17, 695–708 (2013).
Kraakman, M. J. et al. Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes. J. Clin. Invest. 127, 2133–2147 (2017).
Flynn, M. C. et al. Transient intermittent hyperglycemia accelerates atherosclerosis by promoting myelopoiesis. Circ. Res. 127, 877–892 (2020).
Barrett, T. J. et al. Apolipoprotein AI) promotes atherosclerosis regression in diabetic mice by suppressing myelopoiesis and plaque inflammation. Circulation 140, 1170–1184 (2019).
Distel, E. et al. miR33 inhibition overcomes deleterious effects of diabetes mellitus on atherosclerosis plaque regression in mice. Circ. Res. 115, 759–769 (2014).
Mantelmacher, F. D. et al. GIP regulates inflammation and body weight by restraining myeloid-cell-derived S100A8/A9. Nat. Metab. 1, 58–69 (2019).
Swirski, F. K. & Nahrendorf, M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science 339, 161–166 (2013).
Horckmans, M. et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur. Heart J. 38, 187–197 (2017).
Nagareddy, P. R. et al. NETosis is required for S100A8/A9-induced granulopoiesis after myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 40, 2805–2807 (2020).
Marinkovic, G. et al. Inhibition of pro-inflammatory myeloid cell responses by short-term S100A9 blockade improves cardiac function after myocardial infarction. Eur. Heart J. 40, 2713–2723 (2019).
Marinkovic, G. et al. S100A9 links inflammation and repair in myocardial infarction. Circ. Res. 127, 664–676 (2020).
Savchenko, A. S. et al. VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. Blood 123, 141–148 (2014).
Kyaw, T. et al. Alarmin-activated B cells accelerate murine atherosclerosis after myocardial infarction via plasma cell-immunoglobulin-dependent mechanisms. Eur. Heart J. 42, 938–947 (2020).
Dutta, P. et al. Myocardial infarction accelerates atherosclerosis. Nature 487, 325–329 (2012).
Al-Sharea, A., Lee, M. K. S., Purton, L. E., Hawkins, E. D. & Murphy, A. J. The haematopoietic stem cell niche: a new player in cardiovascular disease? Cardiovasc. Res. 115, 277–291 (2019).
Al-Sharea, A. et al. Nicotinic acetylcholine receptor alpha 7 stimulation dampens splenic myelopoiesis and inhibits atherogenesis in Apoe-/- mice. Atherosclerosis 265, 47–53 (2017).
Parganas, E. et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell 93, 385–395 (1998).
Wang, W. et al. Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2 (V617F) mice. Circ. Res. 123, e35–e47 (2018).
Tang, Y. et al. Inhibition of JAK2 suppresses myelopoiesis and atherosclerosis in Apoe-/- mice. Cardiovasc. Drugs Ther. 34, 145–152 (2020).
Lee, M. K. S. et al. Apoptotic ablation of platelets reduces atherosclerosis in mice with diabetes. Arterioscler. Thromb. Vasc. Biol. 41, 1167–1178 (2021).
Meyer, M. A. S. et al. Treatment effects of interleukin-6 receptor antibodies for modulating the systemic inflammatory response after out-of-hospital cardiac arrest (The IMICA Trial): a double-blinded, placebo-controlled, single-center, randomized, clinical trial. Circulation 143, 1841–1851 (2021).
Kraakman, M. J. et al. Targeting gp130 to prevent inflammation and promote insulin action. Diabetes Obes. Metab. 15(Suppl. 3), 170–175 (2013).
Schreiber, S. et al. Therapeutic interleukin 6 trans-signaling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease. Gastroenterology 160, 2354–2366.e11 (2021).
Schuett, H. et al. Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 32, 281–290 (2012).
Scheller, J. & Rose-John, S. The interleukin 6 pathway and atherosclerosis. Lancet 380, 338 (2012).
Taleb, S., Tedgui, A. & Mallat, Z. IL-17 and Th17 cells in atherosclerosis: subtle and contextual roles. Arterioscler. Thromb. Vasc. Biol. 35, 258–264 (2015).
Erbel, C. et al. Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice. J. Immunol. 183, 8167–8175 (2009).
Smith, E. et al. Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice. Circulation 121, 1746–1755 (2010).
Danzaki, K. et al. Interleukin-17A deficiency accelerates unstable atherosclerotic plaque formation in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 32, 273–280 (2012).
Wu, D. et al. Efficacy and safety of interleukin-17 antagonists in patients with plaque psoriasis: a meta-analysis from phase 3 randomized controlled trials. J. Eur. Acad. Dermatol. Venereol. 31, 992–1003 (2017).
Rungapiromnan, W., Yiu, Z. Z. N., Warren, R. B., Griffiths, C. E. M. & Ashcroft, D. M. Impact of biologic therapies on risk of major adverse cardiovascular events in patients with psoriasis: systematic review and meta-analysis of randomized controlled trials. Br. J. Dermatol. 176, 890–901 (2017).
Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013).
Kleinewietfeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518–522 (2013).
Boring, L., Gosling, J., Cleary, M. & Charo, I. F. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394, 894–897 (1998).
Obstfeld, A. E. et al. C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis. Diabetes 59, 916–925 (2010).
Weisberg, S. P. et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 116, 115–124 (2006).
Winter, C. et al. Chrono-pharmacological targeting of the CCL2-CCR2 axis ameliorates atherosclerosis. Cell Metab. 28, 175–182.e5 (2018).
Tacke, F. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194 (2007).
Rahman, K. et al. Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression. J. Clin. Invest. 127, 2904–2915 (2017).
Koenen, R. R. et al. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat. Med. 15, 97–103 (2009).
Hultcrantz, M. et al. Risk and cause of death in patients diagnosed with myeloproliferative neoplasms in Sweden between 1973 and 2005: a population-based study. J. Clin. Oncol. 33, 2288–2295 (2015).
Kumagai, N. et al. Acute coronary syndrome associated with essential thrombocythemia. J. Cardiol. 54, 485–489 (2009).
Murphy, A. J. et al. Deficiency of ATP-binding cassette transporter B6 in megakaryocyte progenitors accelerates atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 34, 751–758 (2014).
Scheffer, M. G., Michiels, J. J., Simoons, M. L. & Roelandt, J. R. Thrombocythemia and coronary artery disease. Am. Heart J. 122, 573–576 (1991).
Machlus, K. R. et al. CCL5 derived from platelets increases megakaryocyte proplatelet formation. Blood 127, 921–926 (2016).
Maggi, P. et al. Effects of therapy with maraviroc on the carotid intima media thickness in HIV-1/HCV Co-infected patients. In Vivo 31, 125–131 (2017).
Piconi, S. et al. Maraviroc reduces arterial stiffness in PI-treated HIV-infected patients. Sci. Rep. 6, 28853 (2016).
Broxmeyer, H. E. et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J. Exp. Med. 201, 1307–1318 (2005).
Liles, W. C. et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood 102, 2728–2730 (2003).
Wang, J., Tannous, B. A., Poznansky, M. C. & Chen, H. CXCR4 antagonist AMD3100 (plerixafor): From an impurity to a therapeutic agent. Pharmacol. Res. 159, 105010 (2020).
Doring, Y. et al. Vascular CXCR4 limits atherosclerosis by maintaining arterial integrity: evidence from mouse and human studies. Circulation 136, 388–403 (2017).
Doring, Y. et al. CXCL12 derived from endothelial cells promotes atherosclerosis to drive coronary artery disease. Circulation 139, 1338–1340 (2019).
Doring, Y. et al. B-Cell-Specific CXCR4 protects against atherosclerosis development and increases plasma IgM levels. Circ. Res. 126, 787–788 (2020).
Fredman, G. et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat. Commun. 7, 12859 (2016).
Gerlach, B. D. et al. Resolvin D1 promotes the targeting and clearance of necroptotic cells. Cell Death Differ. 27, 525–539 (2020).
Brennan, E. P. et al. Lipoxins protect against inflammation in diabetes-associated atherosclerosis. Diabetes 67, 2657–2667 (2018).
Fredman, G. & Tabas, I. Boosting inflammation resolution in atherosclerosis: the next frontier for therapy. Am. J. Pathol. 187, 1211–1221 (2017).
Claria, J., Dalli, J., Yacoubian, S., Gao, F. & Serhan, C. N. Resolvin D1 and resolvin D2 govern local inflammatory tone in obese fat. J. Immunol. 189, 2597–2605 (2012).
Man, K. et al. The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat. Immunol. 14, 1155–1165 (2013).
Shi, L. Z. et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376 (2011).
Vasanthakumar, A. et al. Sex-specific adipose tissue imprinting of regulatory T cells. Nature 579, 581–585 (2020).
Huang, S. C. et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat. Immunol. 15, 846–855 (2014).
Huang, S. C. et al. Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation. Immunity 45, 817–830 (2016).
Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015).
Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457–470.e13 (2016).
Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496, 238–242 (2013).
Palmieri, E. M. et al. Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase. Nat. Commun. 11, 698 (2020).
Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018).
Cordes, T. et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 291, 14274–14284 (2016).
Ip, W. K. E., Hoshi, N., Shouval, D. S., Snapper, S. & Medzhitov, R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356, 513–519 (2017).
Sarrazy, V. et al. Disruption of glut1 in hematopoietic stem cells prevents myelopoiesis and enhanced glucose flux in atheromatous plaques of ApoE–/– mice. Circ. Res. 118, 1062–1077 (2016).
Dumont, A., Lee, M., Barouillet, T., Murphy, A. & Yvan-Charvet, L. Mitochondria orchestrate macrophage effector functions in atherosclerosis. Mol. Asp. Med. 77, 100922 (2021).
van den Berg, S. M. et al. Blocking CD40-TRAF6 interactions by small-molecule inhibitor 6860766 ameliorates the complications of diet-induced obesity in mice. Int. J. Obes. 39, 782–790 (2015).
Seijkens, T. T. P. et al. Targeting CD40-induced TRAF6 signaling in macrophages reduces atherosclerosis. J. Am. Coll. Cardiol. 71, 527–542 (2018).
Chatzigeorgiou, A. et al. Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance. Proc. Natl Acad. Sci. USA 111, 2686–2691 (2014).
Cipollone, F. et al. Preprocedural level of soluble CD40L is predictive of enhanced inflammatory response and restenosis after coronary angioplasty. Circulation 108, 2776–2782 (2003).
Fu, Q. et al. A novel function of platelets and CD40L in NAFLD-promoted HCC development. J. Immunol. 200 (Suppl. 1), 56.16 (2018).
Ma, C. et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531, 253–257 (2016).
Ma, K. et al. CTLA4-IgG ameliorates homocysteine-accelerated atherosclerosis by inhibiting T-cell overactivation in apoE–/– mice. Cardiovasc. Res. 97, 349–359 (2013).
Kang, E. H. et al. Comparative cardiovascular risk of abatacept and tumor necrosis factor inhibitors in patients with rheumatoid arthritis with and without diabetes mellitus: a multidatabase cohort study. J. Am. Heart Assoc. 7, e007393 (2018).
Vanrenterghem, Y. et al. Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation 91, 976–983 (2011).
Drobni, Z. D. et al. Association between immune checkpoint inhibitors with cardiovascular events and atherosclerotic plaque. Circulation 142, 2299–2311 (2020).
Calabretta, R. et al. Immune checkpoint inhibitor therapy induces inflammatory activity in large arteries. Circulation 142, 2396–2398 (2020).
Poels, K. et al. Antibody-mediated inhibition of CTLA4 aggravates atherosclerotic plaque inflammation and progression in hyperlipidemic mice. Cells 9, 1987 (2020).
Poels, K. et al. Immune checkpoint inhibitor therapy aggravates T cell-driven plaque inflammation in atherosclerosis. J. Am. Coll. Cardiol. CardioOncol. 2, 599–610 (2020).
Ley, K. & Roy, P. Blind Spot: 18F-FDG PET Fails to reveal atherosclerosis aggravated by cancer immunotherapy. J. Am. Coll. Cardiol. CardioOncol. 2, 611–613 (2020).
Kondapalli, L., Bottinor, W. & Lenneman, C. By releasing the brakes with immunotherapy, are we accelerating atherosclerosis? Circulation 142, 2312–2315 (2020).
Todoric, J. et al. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat. Metab. 2, 1034–1045 (2020).
Mason, K. D. et al. Programmed anuclear cell death delimits platelet life span. Cell 128, 1173–1186 (2007).
Oieni, J. et al. Nano-Ghosts: biomimetic membranal vesicles, technology and characterization. Methods 177, 126–134 (2020).
Zhao, Z., Ukidve, A., Kim, J. & Mitragotri, S. Targeting strategies for tissue-specific drug delivery. Cell 181, 151–167 (2020).
Kanarek, N., Petrova, B. & Sabatini, D. M. Dietary modifications for enhanced cancer therapy. Nature 579, 507–517 (2020).
Acknowledgements
M.A.F. is supported by a Senior Principal Research Fellowship of the National Health & Medical Research Council (NHMRC) of Australia (APP1116936) and an NHMRC Investigator grant (APP1194141). A.J.M. is supported by a CSL Centenary Award and an NHMRC Investigator grant (APP1194329).
Author information
Authors and Affiliations
Contributions
The authors contributed equally to the writing and revision of the article. A.J.M. prepared the draft figures that were used as a guide for the final images.
Corresponding authors
Ethics declarations
Competing Interests
The authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Immunology thanks K. Moore, F. Swirski and C. Weber for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Murphy, A.J., Febbraio, M.A. Immune-based therapies in cardiovascular and metabolic diseases: past, present and future. Nat Rev Immunol 21, 669–679 (2021). https://doi.org/10.1038/s41577-021-00580-5
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41577-021-00580-5
This article is cited by
-
Role of oxidative stress and inflammation-related signaling pathways in doxorubicin-induced cardiomyopathy
Cell Communication and Signaling (2023)
-
Nanotechnology for Enhanced Cytoplasmic and Organelle Delivery of Bioactive Molecules to Immune Cells
Pharmaceutical Research (2022)
-
Racial Disparities and Cardiometabolic Risk: New Horizons of Intervention and Prevention
Current Diabetes Reports (2022)
-
Immune discovery aplenty at twenty
Nature Reviews Immunology (2021)