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. 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European Heart Journal – Oxford University Press
Published: May 15, 2018
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