Is defective cholesterol efflux an integral inflammatory component in myelopoiesis-driven cardiovascular diseases?

Is defective cholesterol efflux an integral inflammatory component in myelopoiesis-driven... Abstract View largeDownload slide View largeDownload slide This editorial refers to ‘Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis’†, by D. Dragoljevic et al., on page 2158. In this issue of the European Heart Journal, Dragoljevic et al. show that myelopoiesis is an inflammatory intermediate in rheumatoid arthritis (RA) dominated by defective cholesterol efflux pathways in haematopoietic and myeloid progenitors.1 As a consequence, enhanced peripheral myeloid cells contribute to accelerated atherosclerosis and impaired lesion regression. These findings provide a novel example on how enhanced myelopoiesis ties chronic inflammatory diseases to cardiovascular diseases (CVD). Reduced cellular cholesterol efflux promotes monocytosis in RA beyond traditional risk factors for CVD Rheumatoid arthritis is associated with a >50% increase in cardiovascular morbidity and mortality compared with the general population.2,3 The cause of accelerated atherosclerosis in RA is still not fully understood, but can be partially attributed to a higher prevalence of traditional risk factors for CVD, including smoking, hypertension, diabetes mellitus, and obesity.4 However, the contribution of dyslipidaemia to CVD risk in RA has been contradictory in the literature,3 and the beneficial use of LDL-lowering therapy (i.e. statins) in all RA patients cannot yet be supported by evidence.5 An abnormal atherogenic index [total cholesterol:HDL-cholesterol (HDL-C) ratio] has been considered as a predictor of CVD in RA.6 However, HDL-C concentration does not necessarily reflect the dynamic of HDL-C to promote the so-called reverse cholesterol transport in RA.7 Using two different mouse models of RA [i.e. collagen-induced arthritis (CIA) and K/BxN serum transfer models], the study by Dragoljevic et al. shows that defective cellular cholesterol efflux in myeloid progenitors and mature myeloid cells, rather than reduced plasma cholesterol levels, drives myelopoiesis-driven accelerated atherosclerosis and impaired lesion regression. Although the timing of this study did not allow for the upgraded gating strategy to study human blood monocyte subsets,8 the authors clearly confirm an increase in intermediate and inflammatory non-classical monocyte subsets in RA patients along with reduced expression of the cholesterol efflux ATP-binding cassette transporters ABCA1 and ABCG1 in peripheral blood mononuclear cells (PBMCs) of RA patients. Clearly, the study of Dragoljevic et al. provides an important step in translational atherosclerosis research by suggesting that myelopoiesis could be the missing link between RA and CVD risk. Why is myelopoiesis in RA important in CVD? Defective cholesterol efflux pathways have been shown to promote haematopoietic and progenitor cell mobilization and subsequent extramedullary haematopoiesis,9 which generate inflammatory Ly-6Chigh monocytes that infiltrate atherosclerotic lesions and contribute to disease progression.10 Consistent with this, Dragoljevic et al. now report that the enhanced myelopoiesis observed in arthritic mice is associated with an increased immune cell infiltration in lesions contributing to a less stable phenotype with lipid accumulation and decreased collagen formation. Thus, monocytosis, together with pro-inflammatory cytokines on the endothelium in RA,6 probably contributes to leucocyte recruitment into atherosclerotic plaques. The role of Ly-6Chigh monocyte recruitment during lesion regression is still a matter of debate either preventing macrophage removal from atherosclerotic plaque11 or favouring the generation of newly anti-atherogenic M2 macrophages.12 The present study of Dragoljevic et al. shows that enhanced Ly-6Chigh monocyte counts in the K/BxN serum transfer mouse model of RA led to impaired plaque regression. Thus, this work, combined with the published literature on this topic, demonstrates an exquisite link between systemic inflammation and defective cholesterol efflux pathways in haematopoietic and myeloid progenitors in RA, leading to monocytosis and macrophage accumulation in atheromata. Are defective cholesterol efflux pathways in haematopoietic and myeloid progenitors key molecular checkpoints linking inflammation and metabolism to CVD in RA? Chronic inflammation is associated with an increased risk of CVD in RA.2–7 It is generally assumed that residual inflammatory risk is independent of residual cholesterol risk in CVD patients,13 and high C-reactive protein (CRP) levels in RA patients were shown to increase the risk of CVD two-fold.14 However, one of the interesting ideas brought up in the work by Dragoljevic et al. is that RA disease-specific inflammatory factors directly promote defective cholesterol efflux in bone marrow haematopoietic and myeloid progenitors to stimulate their expansion and fate. Consistently, it was previously reported that haematopoietic and myeloid growth factors such as interleukin-3 (IL-3) or granulocye–macrophage colony-stimulating factor (GM-CSF) markedly reduced the expression of the cholesterol efflux ATP-binding cassette transporters ABCA1 and ABCG1 to retain cholesterol for efficient proliferation.15 The present study by Dragoljevic et al. extends these findings by showing similar effects with RA disease non-proliferative factors such as tumour necrosis factor alpha (TNFα) or other interleukins, suggesting a broader implication of this cholesterol efflux pathway in myeloid lineage specification under chronic inflammation or even under emergency myelopoiesis or ‘trained immunity’ characterized by a cytokine storm.16,17 Nevertheless, the underlying mechanism has not yet been fully characterized. Thus, it will be of interest in the future to identify further how this metabolic pathway is controlled by inflammatory cytokines in haematopoietic and myeloid progenitors to limit their expansion and fate in RA disease conditions, especially whether it involves Toll-like receptor signalling pathways.18 During ‘trained immunity’, GM-CSF and IL-1β similarly promote myelopoiesis through a metabolic reprogramming of haematopoietic progenitors involving not only enhanced cholesterol metabolism but also glycolysis.19 We and others previously found that a synergistic effect of glycolysis and defective cholesterol efflux pathways is required for GM-CSF-induced haematopoietic stem cell proliferation and myeloid lineage commitment.20,21 The metabolic need for IL-1β in promoting proliferation and myeloid differentiation in haematopoietic stem cells is less clear, but requires a PU.1-dependent myeloid gene programme22 that could be induced by genetic reprogramming after Western diet- and leptin deficiency-induced obesity23,24 or clonal haematopoiesis associated with ageing.25 Thus, the findings of Dragoljevic et al. could be extended beyond RA and may reflect a general mechanism whereby chronic inflammatory diseases metabolically control myelopoiesis-driven CVD (Take home figure). Take home figure View largeDownload slide Inflammatory cues induce a metabolic-dependent myelopoiesis shift in lineage commitment contributing to atherogenesis. The cartoon illustrates the potential contribution of pathological acute and chronic inflammatory diseases towards shifting the bone marrow myelopoietic flexibility and supplying myeloid cells peripherally for extramedullary myelopoiesis in the spleen and contributing to atherosclerosis progression and complication. The underlying mechanism may involve a metabolic rewiring of haematopoietic progenitors by inflammatory cues such as interleukin 1β (IL-1β) secondary to Nlrp3 inflammasome activation or Tet2-dependent epigenetic modulation, granulocye–macrophage colony-stimulating factor (GM-CSF), or tumour necrosis factor α (TNFα). Whether reduced ATP-binding cassette A1 (ABCA1)- and ABCG1-dependent cholesterol efflux pathways or enhanced glycolytic activity during myelopoiesis are driven by an interaction between the transcriptional factor PU.1, downstream of inflammatory cues, and the nuclear liver X receptor (LXR) remains to be investigated. Take home figure View largeDownload slide Inflammatory cues induce a metabolic-dependent myelopoiesis shift in lineage commitment contributing to atherogenesis. The cartoon illustrates the potential contribution of pathological acute and chronic inflammatory diseases towards shifting the bone marrow myelopoietic flexibility and supplying myeloid cells peripherally for extramedullary myelopoiesis in the spleen and contributing to atherosclerosis progression and complication. The underlying mechanism may involve a metabolic rewiring of haematopoietic progenitors by inflammatory cues such as interleukin 1β (IL-1β) secondary to Nlrp3 inflammasome activation or Tet2-dependent epigenetic modulation, granulocye–macrophage colony-stimulating factor (GM-CSF), or tumour necrosis factor α (TNFα). Whether reduced ATP-binding cassette A1 (ABCA1)- and ABCG1-dependent cholesterol efflux pathways or enhanced glycolytic activity during myelopoiesis are driven by an interaction between the transcriptional factor PU.1, downstream of inflammatory cues, and the nuclear liver X receptor (LXR) remains to be investigated. Clinical perspectives In RA, the use of biological TNF inhibitors and non-biological methotrexate is associated with a decreased risk of CVD, while corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk.26 Thus, the study of Dragoljevic et al. arms researchers with new perspectives to test the effect of medications on monocyte counts in RA patients. The present study also raises the question of the potential synergy of targeting residual inflammatory risk on top of standard CVD risk in RA patients. Interestingly, the CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcomes Study) has recently provided the first large-scale study to show that targeting IL-1β can confer cardiovascular benefit in very high-risk patients with previous myocardial infarction and a prolonged inflammatory signal (hs-CRP >2 mg/L), setting the stage for a new chapter of therapeutic opportunity.27 However, as recently discussed by Ridker,28 there is a need for a dedicated randomized trial to test for a synergistic effect of anti-inflammatory and other CVD therapies, especially if these pathways are as interconnected as the present study by Dragoljevic et al. suggests. Funding This work was supported by grants from the INSERM Atip-Avenir program, the association VML (Vaincre les Maladies Lysosomales), the Fondation de France (FDF), the European Marie Curie program (CIG-630926), the Agence Nationale de la Recherche (ANR-14-CE12-0017-01), and the European Research Council (ERC) consolidator programme (ERC2016COG724838) to L.Y.C. Conflict of interest: none declared. References 1 Dragoljevic D , Kraakman MJ , Nagareddy PR , Ngo D , Shihata W , Kammoun HL , Whillas A , Lee MKS , Al-Sharea A , Pernes G , Flynn MC , Lancaster GI , Febbraio MA , Chin-Dusting J , Hanaoka BY , Wicks IP , Murphy AJ. Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis . Eur Heart J 2018 ; 39 : 2158 – 2167 . 2 Mason JC , Libby P. Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions . Eur Heart J 2015 ; 36 : 482 – 489 . Google Scholar CrossRef Search ADS PubMed 3 Tournadre A , Mathieu S , Soubrier M. Managing cardiovascular risk in patients with inflammatory arthritis: practical considerations . Ther Adv Musculoskelet Dis 2016 : 8 : 180 – 191 . Google Scholar CrossRef Search ADS PubMed 4 Skeoch S , Bruce IN. Atherosclerosis in rheumatoid arthritis: is it all about inflammation? Nat Rev Rheumatol 2015 : 11 : 390 – 400 . Google Scholar CrossRef Search ADS PubMed 5 Soulaidopoulos S , Nikiphorou E , Dimitroulas T , Kitas GD. The role of statins in disease modification and cardiovascular risk in rheumatoid arthritis . Front Med 2018 ; 5 : 24 . Google Scholar CrossRef Search ADS 6 Choy E , Ganeshalingam K , Sem AG , 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 2014 : 53 : 2143 – 2154 . Google Scholar CrossRef Search ADS PubMed 7 Tall AR , Yvan-Charvet L. Cholesterol, inflammation and innate immunity . Nat Rev Immunol 2015 ; 15 : 104 – 116 . Google Scholar CrossRef Search ADS PubMed 8 Thomas GD , Hamers AAJ , Nakao C , Marcovecchio P , Taylor AM , McSkimming C , Nguyen AT , McNamara CA , Hedrick CC. Human blood monocyte subsets: a new gating strategy defined using cell surface markers identified by mass cytometry . Arterioscler Thromb Vasc Biol 2017 ; 37 : 154 – 158 . 9 Westerterp M , Gourion-Arsiquaud S , Murphy AM , Shih A , Cremers S , Levine RL , Tall AR , Yvan-Charvet L. Regulation of hematopoietic stem and progenitor cell mobilization by cholesterol efflux pathways . Cell Stem Cell 2012 ; 11 : 195 – 206 . Google Scholar CrossRef Search ADS PubMed 10 Robbins CS , Chudnovskiy A , Rauch PJ , Figueiredo JL , Iwamoto Y , Gorbatov R , Etzrodt M , Weber GF , Ueno T , van Rooijen N , Mulligan-Kehoe MJ , Libby P , Nahrendorf M , Pittet MJ , Weissleder R , Swirski FK. Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrates atherosclerotic lesions . Circulation 2012 ; 125 : 364 – 374 . Google Scholar CrossRef Search ADS PubMed 11 Potteaux S , Gautier EL , Hutchison SB , van Rooijen N , Rader DJ , Thomas MJ , Sorci-Thomas MG , Randolph GJ. Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of ApoE–/– mice during disease regression . J Clin Invest 2011 ; 121 : 2025 – 2036 . Google Scholar CrossRef Search ADS PubMed 12 Rahman K , Vengrenyuk Y , Ramsey SA , Vila NR , Girgis NM , Liu J , Gusarova V , Gromada J , Weinstock A , Moore KJ , Loke P , Fisher EA. Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression . J Clin Invest 2017 ; 127 : 2904 – 2915 . Google Scholar CrossRef Search ADS PubMed 13 Ridker PM. Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin . Eur Heart J 2016 ; 37 : 1720 – 1722 . Google Scholar CrossRef Search ADS PubMed 14 Zhang J , Chen L , Delzell E , Muntner P , Hillegass WB , Safford MM , Millan IY , Crowson CS , Curtis JR. The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis . Ann Rheum Dis 2014 ; 73 : 1301 – 1308 . Google Scholar CrossRef Search ADS PubMed 15 Yvan-Charvet L , Pagler T , Gautier EL , Avagyan S , Siry RL , Han S , Welch CL , Wang N , Randolph GJ , Snoeck HW , Tall AR. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 2010 ; 328 : 1689 – 1693 . Google Scholar CrossRef Search ADS PubMed 16 Boettcher S , Manz MG. Regulation of inflammation- and infection-driven hematopoiesis . Trends Immunol 2017 ; 38 : 345 – 357 . Google Scholar CrossRef Search ADS PubMed 17 Netea MG , Joosten LA , Latz E , Mills KH , Natoli G , Stunnenberg HG , O’Neill LA , Xavier RJ. Trained immunity: a program of innate immune memory in health and disease . Science 2016 ; 352 :aaf1098. 18 Joosten LA , Abdollahi-Roodsaz S , Dinarello CA , O’Neill L , Netea MG. Toll-like receptors and chronic inflammation in rheumatic diseases: new developments . Nat Rev Rheumatol 2016 ; 12 : 344 – 357 . Google Scholar CrossRef Search ADS PubMed 19 Mitroulis I , Ruppova K , Wang B , Chen LS , Grzybek M , Grinenko T , Eugster A , Troullinaki M , Palladini A , Kourtzelis I , Chatzigeorgiou A , Schlitzer A , Beyer M , Joosten LAB , Isermann B , Lesche M , Petzold A , Simons K , Henry I , Dahl A , Schultze JL , Wielockx B , Zamboni N , Mirtschink P , Coskun U , Hajishengallis G , Netea G , Chavakis T. Modulation of myelopoiesis progenitoprs is an integral component of trained immunity . Cell 2018 ; 172 : 147 – 161 . Google Scholar CrossRef Search ADS PubMed 20 Sarrazy V , Viaud M , Westerterp M , Ivanov S , Giorgetti-Peraldi S , Guinamard R , Gautier EL , Thorp EB , De Vivo DC , Yvan-Charvet L. Disruption of Glut1 in hematopoietic stem cells prevents myelopoiesis and enhanced glucose flux in atheromatous plaques of ApoE–/– mice . Circ Res 2016 ; 118 : 1062 – 1077 . Google Scholar CrossRef Search ADS PubMed 21 Oburoglu L , Tardito S , Fritz V , de Barros SC , Merida P , Craveiro M , Mamede J , Cretenet G , Mongellaz C , An X , Klysz D , Touhami J , Boyer-Clavel M , Battini JL , Dardalhon V , Zimmermann VS , Mohandas N , Gottlieb E , Sitbon M , Kinet S , Taylor N. Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification . Cell Stem Cell 2014 ; 15 : 169 – 184 . Google Scholar CrossRef Search ADS PubMed 22 Pietras EM , Mirantes-Barbeito C , Fong S , Loeffler D , Kovtonyuk LV , Zhang S , Lakshminarasimhan R , Chin CP , Techner JM , Will B , Nerlov C , Steidl U , Manz MG , Schroeder T , Passegué E. Chronic interleukin-1 drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal . Nat Cell Biol 2016 ; 18 : 607 – 618 . Google Scholar CrossRef Search ADS PubMed 23 Nagareddy PR , Kraakman M , Masters SL , Stirzaker RA , Gorman DJ , Grant RW , Dragoljevic D , Hong ES , Abdel-Latif A , Smyth SS , Choi SH , Korner J , Bornfeldt KE , Fisher EA , Dixit VD , Tall AR , Goldberg IJ , Murphy AJ. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity . Cell Metab 2014 ; 19 : 821 – 835 . Google Scholar CrossRef Search ADS PubMed 24 Christ A , Gunther P , Lauterbach MAR , Duewell P , Biswas D , Pelka K , Scholz CJ , Oosting M , Haendler K , Babler K , Klee K , Schulte-Schrepping J , Ilas T Moorlag SJCFM Kumar V , Park MH , Joosten LAB , Groh LA , Riksen NP , Espevik T , Schlitzer A , Li Y , Fitzgerald ML , Netea MG , Schultze JL , Latz E. Western diet triggers NLRP3-dependent innate immune reprogramming . Cell 2018 ; 172 : 162 – 175 . Google Scholar CrossRef Search ADS PubMed 25 Fuster JJ , MacLauchlan S , Zuriaga MA , Polackal MN , Ostriker AC , Chakraborty R , Wu CL , Sano S , Muralidharan S , Rius C , Vuong J , Jacob S , Muralidhar V , Roberstson AA , Cooper MA , Andrés V , Hirschi KK , Martin KA , Walsh K. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice . Science 2017 ; 355 : 842 – 847 . Google Scholar CrossRef Search ADS PubMed 26 Roubille C , Richer V , Starnino T , McCourt C , McFarlane A , Fleming P , Siu S , Kraft J , Lynde C , Pope J , Gulliver W , Keeling S , Dutz J , Bessette L , Bissonnette R , Haraoui B. The effects of tumor necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis . Ann Rheum Dis 2015 ; 74 : 480 – 489 . Google Scholar CrossRef Search ADS PubMed 27 Ridker PM , Everett BM , Thuren T , MacFadyen JG , Chang WH , Ballantyne C , Fonseca F , Nicolau J , Koening W , Anker SD , Kastelein JJP , Cornel JH , Pais P , Pella D , Genest J , Cifkova R , Lorenzatti A , Forster T , Kobalava Z , Vida-Simiti L , Flather M , Shimokawa H , Ogawa H , Dellborg M , Rossi PRF , Troquay RPT , Libby P , Glynn RJ ; CANTOS Trial Group . Antiinflammatory therapy with canakinumab for atherosclerotic disease . N Engl J Med 2017 ; 377 : 1119 – 1131 . Google Scholar CrossRef Search ADS PubMed 28 Ridker PM. Mortality differences associated with treatment responses in CANTOS and FOURIER: insights and implications . Circulation 2018 ; 137 : 1763 – 1766 . Google Scholar PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

Is defective cholesterol efflux an integral inflammatory component in myelopoiesis-driven cardiovascular diseases?

Loading next page...
 
/lp/ou_press/is-defective-cholesterol-efflux-an-integral-inflammatory-component-in-BtAPaZfwU1
Publisher
Oxford University Press
Copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
ISSN
0195-668X
eISSN
1522-9645
D.O.I.
10.1093/eurheartj/ehy269
Publisher site
See Article on Publisher Site

Abstract

Abstract View largeDownload slide View largeDownload slide This editorial refers to ‘Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis’†, by D. Dragoljevic et al., on page 2158. In this issue of the European Heart Journal, Dragoljevic et al. show that myelopoiesis is an inflammatory intermediate in rheumatoid arthritis (RA) dominated by defective cholesterol efflux pathways in haematopoietic and myeloid progenitors.1 As a consequence, enhanced peripheral myeloid cells contribute to accelerated atherosclerosis and impaired lesion regression. These findings provide a novel example on how enhanced myelopoiesis ties chronic inflammatory diseases to cardiovascular diseases (CVD). Reduced cellular cholesterol efflux promotes monocytosis in RA beyond traditional risk factors for CVD Rheumatoid arthritis is associated with a >50% increase in cardiovascular morbidity and mortality compared with the general population.2,3 The cause of accelerated atherosclerosis in RA is still not fully understood, but can be partially attributed to a higher prevalence of traditional risk factors for CVD, including smoking, hypertension, diabetes mellitus, and obesity.4 However, the contribution of dyslipidaemia to CVD risk in RA has been contradictory in the literature,3 and the beneficial use of LDL-lowering therapy (i.e. statins) in all RA patients cannot yet be supported by evidence.5 An abnormal atherogenic index [total cholesterol:HDL-cholesterol (HDL-C) ratio] has been considered as a predictor of CVD in RA.6 However, HDL-C concentration does not necessarily reflect the dynamic of HDL-C to promote the so-called reverse cholesterol transport in RA.7 Using two different mouse models of RA [i.e. collagen-induced arthritis (CIA) and K/BxN serum transfer models], the study by Dragoljevic et al. shows that defective cellular cholesterol efflux in myeloid progenitors and mature myeloid cells, rather than reduced plasma cholesterol levels, drives myelopoiesis-driven accelerated atherosclerosis and impaired lesion regression. Although the timing of this study did not allow for the upgraded gating strategy to study human blood monocyte subsets,8 the authors clearly confirm an increase in intermediate and inflammatory non-classical monocyte subsets in RA patients along with reduced expression of the cholesterol efflux ATP-binding cassette transporters ABCA1 and ABCG1 in peripheral blood mononuclear cells (PBMCs) of RA patients. Clearly, the study of Dragoljevic et al. provides an important step in translational atherosclerosis research by suggesting that myelopoiesis could be the missing link between RA and CVD risk. Why is myelopoiesis in RA important in CVD? Defective cholesterol efflux pathways have been shown to promote haematopoietic and progenitor cell mobilization and subsequent extramedullary haematopoiesis,9 which generate inflammatory Ly-6Chigh monocytes that infiltrate atherosclerotic lesions and contribute to disease progression.10 Consistent with this, Dragoljevic et al. now report that the enhanced myelopoiesis observed in arthritic mice is associated with an increased immune cell infiltration in lesions contributing to a less stable phenotype with lipid accumulation and decreased collagen formation. Thus, monocytosis, together with pro-inflammatory cytokines on the endothelium in RA,6 probably contributes to leucocyte recruitment into atherosclerotic plaques. The role of Ly-6Chigh monocyte recruitment during lesion regression is still a matter of debate either preventing macrophage removal from atherosclerotic plaque11 or favouring the generation of newly anti-atherogenic M2 macrophages.12 The present study of Dragoljevic et al. shows that enhanced Ly-6Chigh monocyte counts in the K/BxN serum transfer mouse model of RA led to impaired plaque regression. Thus, this work, combined with the published literature on this topic, demonstrates an exquisite link between systemic inflammation and defective cholesterol efflux pathways in haematopoietic and myeloid progenitors in RA, leading to monocytosis and macrophage accumulation in atheromata. Are defective cholesterol efflux pathways in haematopoietic and myeloid progenitors key molecular checkpoints linking inflammation and metabolism to CVD in RA? Chronic inflammation is associated with an increased risk of CVD in RA.2–7 It is generally assumed that residual inflammatory risk is independent of residual cholesterol risk in CVD patients,13 and high C-reactive protein (CRP) levels in RA patients were shown to increase the risk of CVD two-fold.14 However, one of the interesting ideas brought up in the work by Dragoljevic et al. is that RA disease-specific inflammatory factors directly promote defective cholesterol efflux in bone marrow haematopoietic and myeloid progenitors to stimulate their expansion and fate. Consistently, it was previously reported that haematopoietic and myeloid growth factors such as interleukin-3 (IL-3) or granulocye–macrophage colony-stimulating factor (GM-CSF) markedly reduced the expression of the cholesterol efflux ATP-binding cassette transporters ABCA1 and ABCG1 to retain cholesterol for efficient proliferation.15 The present study by Dragoljevic et al. extends these findings by showing similar effects with RA disease non-proliferative factors such as tumour necrosis factor alpha (TNFα) or other interleukins, suggesting a broader implication of this cholesterol efflux pathway in myeloid lineage specification under chronic inflammation or even under emergency myelopoiesis or ‘trained immunity’ characterized by a cytokine storm.16,17 Nevertheless, the underlying mechanism has not yet been fully characterized. Thus, it will be of interest in the future to identify further how this metabolic pathway is controlled by inflammatory cytokines in haematopoietic and myeloid progenitors to limit their expansion and fate in RA disease conditions, especially whether it involves Toll-like receptor signalling pathways.18 During ‘trained immunity’, GM-CSF and IL-1β similarly promote myelopoiesis through a metabolic reprogramming of haematopoietic progenitors involving not only enhanced cholesterol metabolism but also glycolysis.19 We and others previously found that a synergistic effect of glycolysis and defective cholesterol efflux pathways is required for GM-CSF-induced haematopoietic stem cell proliferation and myeloid lineage commitment.20,21 The metabolic need for IL-1β in promoting proliferation and myeloid differentiation in haematopoietic stem cells is less clear, but requires a PU.1-dependent myeloid gene programme22 that could be induced by genetic reprogramming after Western diet- and leptin deficiency-induced obesity23,24 or clonal haematopoiesis associated with ageing.25 Thus, the findings of Dragoljevic et al. could be extended beyond RA and may reflect a general mechanism whereby chronic inflammatory diseases metabolically control myelopoiesis-driven CVD (Take home figure). Take home figure View largeDownload slide Inflammatory cues induce a metabolic-dependent myelopoiesis shift in lineage commitment contributing to atherogenesis. The cartoon illustrates the potential contribution of pathological acute and chronic inflammatory diseases towards shifting the bone marrow myelopoietic flexibility and supplying myeloid cells peripherally for extramedullary myelopoiesis in the spleen and contributing to atherosclerosis progression and complication. The underlying mechanism may involve a metabolic rewiring of haematopoietic progenitors by inflammatory cues such as interleukin 1β (IL-1β) secondary to Nlrp3 inflammasome activation or Tet2-dependent epigenetic modulation, granulocye–macrophage colony-stimulating factor (GM-CSF), or tumour necrosis factor α (TNFα). Whether reduced ATP-binding cassette A1 (ABCA1)- and ABCG1-dependent cholesterol efflux pathways or enhanced glycolytic activity during myelopoiesis are driven by an interaction between the transcriptional factor PU.1, downstream of inflammatory cues, and the nuclear liver X receptor (LXR) remains to be investigated. Take home figure View largeDownload slide Inflammatory cues induce a metabolic-dependent myelopoiesis shift in lineage commitment contributing to atherogenesis. The cartoon illustrates the potential contribution of pathological acute and chronic inflammatory diseases towards shifting the bone marrow myelopoietic flexibility and supplying myeloid cells peripherally for extramedullary myelopoiesis in the spleen and contributing to atherosclerosis progression and complication. The underlying mechanism may involve a metabolic rewiring of haematopoietic progenitors by inflammatory cues such as interleukin 1β (IL-1β) secondary to Nlrp3 inflammasome activation or Tet2-dependent epigenetic modulation, granulocye–macrophage colony-stimulating factor (GM-CSF), or tumour necrosis factor α (TNFα). Whether reduced ATP-binding cassette A1 (ABCA1)- and ABCG1-dependent cholesterol efflux pathways or enhanced glycolytic activity during myelopoiesis are driven by an interaction between the transcriptional factor PU.1, downstream of inflammatory cues, and the nuclear liver X receptor (LXR) remains to be investigated. Clinical perspectives In RA, the use of biological TNF inhibitors and non-biological methotrexate is associated with a decreased risk of CVD, while corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk.26 Thus, the study of Dragoljevic et al. arms researchers with new perspectives to test the effect of medications on monocyte counts in RA patients. The present study also raises the question of the potential synergy of targeting residual inflammatory risk on top of standard CVD risk in RA patients. Interestingly, the CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcomes Study) has recently provided the first large-scale study to show that targeting IL-1β can confer cardiovascular benefit in very high-risk patients with previous myocardial infarction and a prolonged inflammatory signal (hs-CRP >2 mg/L), setting the stage for a new chapter of therapeutic opportunity.27 However, as recently discussed by Ridker,28 there is a need for a dedicated randomized trial to test for a synergistic effect of anti-inflammatory and other CVD therapies, especially if these pathways are as interconnected as the present study by Dragoljevic et al. suggests. Funding This work was supported by grants from the INSERM Atip-Avenir program, the association VML (Vaincre les Maladies Lysosomales), the Fondation de France (FDF), the European Marie Curie program (CIG-630926), the Agence Nationale de la Recherche (ANR-14-CE12-0017-01), and the European Research Council (ERC) consolidator programme (ERC2016COG724838) to L.Y.C. Conflict of interest: none declared. References 1 Dragoljevic D , Kraakman MJ , Nagareddy PR , Ngo D , Shihata W , Kammoun HL , Whillas A , Lee MKS , Al-Sharea A , Pernes G , Flynn MC , Lancaster GI , Febbraio MA , Chin-Dusting J , Hanaoka BY , Wicks IP , Murphy AJ. Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis . Eur Heart J 2018 ; 39 : 2158 – 2167 . 2 Mason JC , Libby P. Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions . Eur Heart J 2015 ; 36 : 482 – 489 . Google Scholar CrossRef Search ADS PubMed 3 Tournadre A , Mathieu S , Soubrier M. Managing cardiovascular risk in patients with inflammatory arthritis: practical considerations . Ther Adv Musculoskelet Dis 2016 : 8 : 180 – 191 . Google Scholar CrossRef Search ADS PubMed 4 Skeoch S , Bruce IN. Atherosclerosis in rheumatoid arthritis: is it all about inflammation? Nat Rev Rheumatol 2015 : 11 : 390 – 400 . Google Scholar CrossRef Search ADS PubMed 5 Soulaidopoulos S , Nikiphorou E , Dimitroulas T , Kitas GD. The role of statins in disease modification and cardiovascular risk in rheumatoid arthritis . Front Med 2018 ; 5 : 24 . Google Scholar CrossRef Search ADS 6 Choy E , Ganeshalingam K , Sem AG , 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 2014 : 53 : 2143 – 2154 . Google Scholar CrossRef Search ADS PubMed 7 Tall AR , Yvan-Charvet L. Cholesterol, inflammation and innate immunity . Nat Rev Immunol 2015 ; 15 : 104 – 116 . Google Scholar CrossRef Search ADS PubMed 8 Thomas GD , Hamers AAJ , Nakao C , Marcovecchio P , Taylor AM , McSkimming C , Nguyen AT , McNamara CA , Hedrick CC. Human blood monocyte subsets: a new gating strategy defined using cell surface markers identified by mass cytometry . Arterioscler Thromb Vasc Biol 2017 ; 37 : 154 – 158 . 9 Westerterp M , Gourion-Arsiquaud S , Murphy AM , Shih A , Cremers S , Levine RL , Tall AR , Yvan-Charvet L. Regulation of hematopoietic stem and progenitor cell mobilization by cholesterol efflux pathways . Cell Stem Cell 2012 ; 11 : 195 – 206 . Google Scholar CrossRef Search ADS PubMed 10 Robbins CS , Chudnovskiy A , Rauch PJ , Figueiredo JL , Iwamoto Y , Gorbatov R , Etzrodt M , Weber GF , Ueno T , van Rooijen N , Mulligan-Kehoe MJ , Libby P , Nahrendorf M , Pittet MJ , Weissleder R , Swirski FK. Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrates atherosclerotic lesions . Circulation 2012 ; 125 : 364 – 374 . Google Scholar CrossRef Search ADS PubMed 11 Potteaux S , Gautier EL , Hutchison SB , van Rooijen N , Rader DJ , Thomas MJ , Sorci-Thomas MG , Randolph GJ. Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of ApoE–/– mice during disease regression . J Clin Invest 2011 ; 121 : 2025 – 2036 . Google Scholar CrossRef Search ADS PubMed 12 Rahman K , Vengrenyuk Y , Ramsey SA , Vila NR , Girgis NM , Liu J , Gusarova V , Gromada J , Weinstock A , Moore KJ , Loke P , Fisher EA. Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression . J Clin Invest 2017 ; 127 : 2904 – 2915 . Google Scholar CrossRef Search ADS PubMed 13 Ridker PM. Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin . Eur Heart J 2016 ; 37 : 1720 – 1722 . Google Scholar CrossRef Search ADS PubMed 14 Zhang J , Chen L , Delzell E , Muntner P , Hillegass WB , Safford MM , Millan IY , Crowson CS , Curtis JR. The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis . Ann Rheum Dis 2014 ; 73 : 1301 – 1308 . Google Scholar CrossRef Search ADS PubMed 15 Yvan-Charvet L , Pagler T , Gautier EL , Avagyan S , Siry RL , Han S , Welch CL , Wang N , Randolph GJ , Snoeck HW , Tall AR. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 2010 ; 328 : 1689 – 1693 . Google Scholar CrossRef Search ADS PubMed 16 Boettcher S , Manz MG. Regulation of inflammation- and infection-driven hematopoiesis . Trends Immunol 2017 ; 38 : 345 – 357 . Google Scholar CrossRef Search ADS PubMed 17 Netea MG , Joosten LA , Latz E , Mills KH , Natoli G , Stunnenberg HG , O’Neill LA , Xavier RJ. Trained immunity: a program of innate immune memory in health and disease . Science 2016 ; 352 :aaf1098. 18 Joosten LA , Abdollahi-Roodsaz S , Dinarello CA , O’Neill L , Netea MG. Toll-like receptors and chronic inflammation in rheumatic diseases: new developments . Nat Rev Rheumatol 2016 ; 12 : 344 – 357 . Google Scholar CrossRef Search ADS PubMed 19 Mitroulis I , Ruppova K , Wang B , Chen LS , Grzybek M , Grinenko T , Eugster A , Troullinaki M , Palladini A , Kourtzelis I , Chatzigeorgiou A , Schlitzer A , Beyer M , Joosten LAB , Isermann B , Lesche M , Petzold A , Simons K , Henry I , Dahl A , Schultze JL , Wielockx B , Zamboni N , Mirtschink P , Coskun U , Hajishengallis G , Netea G , Chavakis T. Modulation of myelopoiesis progenitoprs is an integral component of trained immunity . Cell 2018 ; 172 : 147 – 161 . Google Scholar CrossRef Search ADS PubMed 20 Sarrazy V , Viaud M , Westerterp M , Ivanov S , Giorgetti-Peraldi S , Guinamard R , Gautier EL , Thorp EB , De Vivo DC , Yvan-Charvet L. Disruption of Glut1 in hematopoietic stem cells prevents myelopoiesis and enhanced glucose flux in atheromatous plaques of ApoE–/– mice . Circ Res 2016 ; 118 : 1062 – 1077 . Google Scholar CrossRef Search ADS PubMed 21 Oburoglu L , Tardito S , Fritz V , de Barros SC , Merida P , Craveiro M , Mamede J , Cretenet G , Mongellaz C , An X , Klysz D , Touhami J , Boyer-Clavel M , Battini JL , Dardalhon V , Zimmermann VS , Mohandas N , Gottlieb E , Sitbon M , Kinet S , Taylor N. Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification . Cell Stem Cell 2014 ; 15 : 169 – 184 . Google Scholar CrossRef Search ADS PubMed 22 Pietras EM , Mirantes-Barbeito C , Fong S , Loeffler D , Kovtonyuk LV , Zhang S , Lakshminarasimhan R , Chin CP , Techner JM , Will B , Nerlov C , Steidl U , Manz MG , Schroeder T , Passegué E. Chronic interleukin-1 drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal . Nat Cell Biol 2016 ; 18 : 607 – 618 . Google Scholar CrossRef Search ADS PubMed 23 Nagareddy PR , Kraakman M , Masters SL , Stirzaker RA , Gorman DJ , Grant RW , Dragoljevic D , Hong ES , Abdel-Latif A , Smyth SS , Choi SH , Korner J , Bornfeldt KE , Fisher EA , Dixit VD , Tall AR , Goldberg IJ , Murphy AJ. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity . Cell Metab 2014 ; 19 : 821 – 835 . Google Scholar CrossRef Search ADS PubMed 24 Christ A , Gunther P , Lauterbach MAR , Duewell P , Biswas D , Pelka K , Scholz CJ , Oosting M , Haendler K , Babler K , Klee K , Schulte-Schrepping J , Ilas T Moorlag SJCFM Kumar V , Park MH , Joosten LAB , Groh LA , Riksen NP , Espevik T , Schlitzer A , Li Y , Fitzgerald ML , Netea MG , Schultze JL , Latz E. Western diet triggers NLRP3-dependent innate immune reprogramming . Cell 2018 ; 172 : 162 – 175 . Google Scholar CrossRef Search ADS PubMed 25 Fuster JJ , MacLauchlan S , Zuriaga MA , Polackal MN , Ostriker AC , Chakraborty R , Wu CL , Sano S , Muralidharan S , Rius C , Vuong J , Jacob S , Muralidhar V , Roberstson AA , Cooper MA , Andrés V , Hirschi KK , Martin KA , Walsh K. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice . Science 2017 ; 355 : 842 – 847 . Google Scholar CrossRef Search ADS PubMed 26 Roubille C , Richer V , Starnino T , McCourt C , McFarlane A , Fleming P , Siu S , Kraft J , Lynde C , Pope J , Gulliver W , Keeling S , Dutz J , Bessette L , Bissonnette R , Haraoui B. The effects of tumor necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis . Ann Rheum Dis 2015 ; 74 : 480 – 489 . Google Scholar CrossRef Search ADS PubMed 27 Ridker PM , Everett BM , Thuren T , MacFadyen JG , Chang WH , Ballantyne C , Fonseca F , Nicolau J , Koening W , Anker SD , Kastelein JJP , Cornel JH , Pais P , Pella D , Genest J , Cifkova R , Lorenzatti A , Forster T , Kobalava Z , Vida-Simiti L , Flather M , Shimokawa H , Ogawa H , Dellborg M , Rossi PRF , Troquay RPT , Libby P , Glynn RJ ; CANTOS Trial Group . Antiinflammatory therapy with canakinumab for atherosclerotic disease . N Engl J Med 2017 ; 377 : 1119 – 1131 . Google Scholar CrossRef Search ADS PubMed 28 Ridker PM. Mortality differences associated with treatment responses in CANTOS and FOURIER: insights and implications . Circulation 2018 ; 137 : 1763 – 1766 . Google Scholar PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

European Heart JournalOxford University Press

Published: May 15, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off