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Role of splenic monocytes in atherosclerosis

Potteaux, Stephanea; Ait-Oufella, Hafida,b; Mallat, Ziada,c

doi: 10.1097/MOL.0000000000000223

Purpose of review This review relates recent findings that highlight the role of the spleen as an active donor of monocytes during inflammation, with a special focus on atherosclerosis.

Recent findings The contribution of hypercholesterolemia and monocytes/macrophages to atherosclerotic lesion formation is undisputable. The origin of plaque macrophages is, however, still a subject of debate as to whether they derive from local amplification of (resident) macrophages or from continuous recruitment and differentiation of monocytes. Recently, the spleen has emerged as an important reservoir of monocytes that contributes to lesion growth. The regulation of monocyte mobilization from the splenic compartment has, therefore, raised a keen interest in understanding the cellular and molecular mechanisms involved in this process.

Summary Impaired regulation of cholesterol metabolism increases the proliferation of hematopoietic stem and progenitor cells in both the bone marrow and the spleen. Recent findings identified the implication of angiotensin II, red pulp macrophages and B-lymphocytes as partners of monocyte expansion in, and mobilization from the spleen. Future studies will help in understanding the mechanisms of monocyte mobilization and its precise roles in atherosclerosis, and whether modulation of the splenic components may become a promising future direction in the prevention and treatment of cardiovascular diseases.

aINSERM UMR-S 970, Paris Cardiovascular Research Center (PARCC), Université Paris Descartes, Sorbonne Paris Cité

bRéanimation médicale, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Paris, France

cDepartment of Medicine, University of Cambridge, Cambridge, UK

Correspondence to Stephane Potteaux, INSERM UMR-S 970, Paris Cardiovascular Research Center (PARCC), 56 Rue Leblanc, 75015 Paris, France. Tel: +33 1 53 98 80 68; fax: +33 1 53 98 79 53; e-mail:

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Atherosclerosis is a chronic inflammatory disease of the arteries that jeopardizes human health as it silently contributes to the occurrence of cardiovascular diseases (CVDs) such as myocardial infarction and stroke. Monocytes and macrophages are the key cellular protagonists of atherosclerotic plaque formation. Monocytes in circulation infiltrate the intima, differentiate into macrophages and participate in foam cell formation and local inflammation. Recent data pointed to the spleen as an important supplier of monocytes that invade the plaque, and identified hypercholesterolemia and angiotensin II (AngII) as crucial actors in this process. In this review, we will recapitulate and discuss recent data that provide evidence for the implication of splenic monocytes in atherosclerosis.

Box 1

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Monocytes and macrophages are important components of the immune-inflammatory system. The commonly admitted dogma, which postulates that monocytes in the bloodstream are the precursors of macrophages in tissues, replenishing them over time [1], has been revisited thanks to the advent of new technologies. Resident tissue macrophages are often derived from embryonic precursors in the yolk sac and/or fetal liver and self-renew in situ, with little or no contribution from circulating blood monocytes. This is the case in lung [2], liver, spleen, brain or peritoneum [3] in which cells expand in situ in response to macrophage colony-stimulating factor (M-CSF) and granulocyte/macrophage colony-stimulating factor, (GM-CSF) [4]. In some other organs, however, such as the adipose tissue or the intestinal mucosa, resident macrophages are thought to originate from constant replenishment by circulating blood monocytes [5].

Monocytes are defined as fully fledged members of the mononuclear phagocyte system, mediating essential functions of innate immunity. Under certain conditions, mostly related to infection or injury, monocytes rapidly traffic to the site of inflammation in which they give rise to macrophages or dendritic cells [6–8]. Thereafter, macrophages phagocyte cell debris, produce inflammatory cytokines, participate in tissue healing and disappear through apoptosis or emigration, helping restore local homeostasis, whereas dendritic cells process antigen material for T-cell priming.

Atherosclerosis is a chronic inflammatory disease of the arterial wall, characterized by the abundant and constant accumulation of lipoproteins and leukocytes, among which macrophages predominate. These latter fail to emigrate [9], and instead, are engorged with cholesterol, become prone to apoptosis and cause plaques to bulk up. Absence of macrophages has been shown to protect hypercholesterolemic ApoE/ mice against atherosclerosis development [10]. The origin of intimal macrophages has raised questions in the past years: do they derive from circulating monocytes or from local precursors? Macrophages show proliferative activity in the intima, both in human and in experimental models of atherosclerosis and thus certainly contribute to plaque growth (Fig. 1) [11–14]. Even before the initiation of atherosclerosis, resident foam cells that resemble dendritic cells are observed just beneath the endothelium, at areas prone to atherosclerotic plaque development [15,16]. They rapidly expand in mice fed a high fat diet [17] and participate in initial plaque expansion (Fig. 1). It was recently even proposed that the rate of macrophage proliferation in plaque might exceed monocyte influx. Even in such a case, dying macrophages need constant replenishment by newly recruited monocytes [13]. The bulk of evidence, ranging from implication of chemokines and chemokine receptors, to in-vivo quantification of monocyte trafficking, has led to the widespread acceptance that recruitment of monocytes dictate phagocyte accumulation in plaques.



At least two subsets of monocytes have been described in humans and mice [18,19]. On the one hand, mouse Ly-6Chigh monocytes show an overall gene expression profile that closely matches the majority of human blood monocytes (CD14++CD16) [19]. They rapidly infiltrate injured tissues and drive chronic inflammation [20,21▪▪]. On the other hand, nonclassical monocytes (Ly-6Clow in mice, CD14+CD16++ in humans) express high levels of CX3CR1 and low levels of CCR2, patrol the resting vasculature and clear damaged endothelial cells [22], populate normal or inflammatory sites and may contribute to wound healing. Short-lived Ly6Chigh monocytes are thought to be precursors of blood Ly6Clow cells and therefore control their abundance in circulation [3,23].

Visualization of circulating monocytes invading the intima of lesion-prone areas in arteries goes back to the 1980s [24]. Now, it is agreed that monocyte recruitment into atherosclerotic lesions is a continuous process [25]. Ly-6Chigh recruitment into the inflamed vessel wall dominates over Ly-6Clow, not only in atherosclerotic plaques [26,27] but also in abdominal aortic aneurysm [28▪] in ApoE−/− mice. Using genetic models of mice deficient for the migratory/survival CCR2, CX3CR1 and CCR5 pathways, we and others have found that Ly-6Chigh and Ly6Clow monocytes provide additive contribution to atherosclerosis formation in ApoE/ mice [29–31]. More recent studies using Nr4A1/ mice which are (partially) deficient in Ly-6Clow monocytes suggested a possible protective function for this monocyte subset in atherosclerosis [32,33]. The contribution of NR4A1 to atherosclerosis is, however, still debated [34], as the absence of NR4A1 gene expression is not entirely specific to Ly6Clow monocytes and also activates Ly-6Chigh monocytes [35,36]. Because monocyte-derived macrophages are highly plastic [37], one could argue that the cytokine environment mainly dictates the phenotype of macrophages in plaque, regardless of their origin. Finally, our data indicate that sustained macrophage accumulation in lesions is dependent upon continuous monocyte recruitment. Indeed, blockade of monocyte infiltration into atherosclerotic plaques (by normalizing cholesterol levels or injecting pertussis toxin) leads to slow disappearance of plaque macrophages because of sustained apoptosis and low level of proliferation in situ[38]. All together, these studies show that circulating monocytes, and mostly those from the Ly6Chigh subset, traffic into the inflamed intima, promote macrophage accumulation and increase plaque size.

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Hypercholesterolemia is the fuel of atherosclerosis formation. High cholesterol levels increase monocyte number in circulation by activating hematopoietic stem and progenitor cell (HSPC) proliferation, making more monocytes available for recruitment into plaques [26,29,39,40]. In ApoE/ mice, total plasma cholesterol correlates with monocyte number and recruitment into plaques [38]. Furthermore, monocyte number in circulation and plaque size are also highly correlated in these mice [41]. Interestingly, in humans, increased circulating monocyte counts have been shown to be an independent risk factor for coronary artery disease [42,43]. ApoE is expressed on the surface of HSPCs and interacts with both ABCA1 that transports excessive cholesterol from membranes to nascent HDL particles, and ABCG1 that transports cholesterol to mature HDL particles. As a result, cholesterol efflux pathways are disrupted and intracellular cholesterol levels increase in HSPCs lacking ApoE, leading to elevated levels of cholesterol-rich lipid rafts and of the common β-subunit of the IL-3 and GM-CSF receptors at the surface of HSPCs. This enhances the proliferation rate of HSPCs in response to the hematopoietic growth factors IL-3 and GM-CSF (Fig. 1). Similar results were found in LDLr/ mice transplantated with Abca1/Abcg1/ bone marrow cells, and to a lower extent in LDLr/ mice [44,45]. In conclusion, through their crucial roles in HSPC proliferation and myeloid cell generation, cholesterol efflux pathways control innate immunity.

During atherosclerosis, HSPCs have been shown to proliferate in the bone marrow and in the spleen, which they most likely colonize in a CXCL12-dependent manner [46]. In agreement with this finding, splenocytes of ApoE/ under HFD contained numerous HSPCs and formed more granulocyte/macrophage colonies than wild-type mice [47]. Recent studies demonstrated that once HSPCs seed the spleen, they might in fact be retained locally, which potentiates the proliferative effect of locally produced growth factors GM-CSF and IL-3 (Fig. 1). In support of this hypothesis, transfer of ApoE/Cbs/ (which lack the common β subunit of the GM-CSF/IL-3 receptor) bone marrow cells to LDLr/ recipient mice decreased HSPC expansion and monocytosis in bone marrow and spleen and reduced atherosclerosis development [48]. Retention cues in the spleen may involve production of AngII [49], or activation of red pulp macrophages that use the adhesion molecule VCAM-1 to physically retain HSPCs [50].

In steady state, the spleen includes up to 25% of all memory B cells and contains a monocyte reservoir that mobilizes in response to acute injury [51]. As stated above, numerous HSPCs are found in the spleen of hypercholesterolemic Apoe/ mice, and CD11b+ myeloid cells expand throughout the red pulp. To address whether the spleen mobilizes monocytes during atherogenesis and contribute to lesion growth, spleen removal and transplantation experiments have been performed. In mice, splenectomy leads to reduced accumulation of monocytes/macrophages in atherosclerotic lesions, suggesting that the spleen regulates monocyte infiltration in plaques [47]. Nevertheless, splenectomy in mice and rabbits induced the development of larger lesions, which was attributed to changes in the immune status because of B-cell depletion and/or increased levels of cholesterol and triglycerides [52,53]. In humans, the relative risk of dying from pneumonia and ischaemic heart disease was significantly increased after splenectomy because of trauma during the Second World War [54]. Because thrombocytosis, hypercoagulability and bacterial infection represent complications of splenectomy [55], these criteria may have accounted for the increased risk of fatal myocardial ischaemia in these patients, regardless of the potential role of monocytes. Interestingly, a follow-up study recently reported the relation between the splenic activity and the incidence of CVD events in patients who had previously undergone positron emission tomography imaging. Noninvasive measure of 18F-fluorodeoxyglucose positron emission tomography, which reflected the metabolic rate of inflammatory cells (i.e., the proliferation rate of HSPCs and monocytes/macrophages), revealed the value of splenic activity as an independent predictor of the CVD incidence [56]. In addition, an autopsy study of patients after myocardial infarction has shown that the accumulation of macrophages in the ischemic heart was conversely associated with a decrease in splenic monocytes [57]. These studies, though not mechanistic, emphasize the potential role of the spleen in deploying monocytes during CVD development.

Currently, very few studies permit quantifying the contribution of spleen to myeloid cells accumulation in vessels during lesion development. One way is to transplant spleens from CD45.1 ApoE/ to recently splenectomized CD45.2 ApoE/ mice. The transplantation requires construction of anastomoses to preserve the blood flow. Following surgery, monitoring of donor CD45.1 splenic monocytes has to be done within the next few days, because the host cells invade rapidly the new spleen [51]. With this technique, Robbins et al.[47] concluded that the spleen contributed to 30% of monocytes, all Ly6Chigh, accumulated in the aorta. Within the first couple of days after spleen transplantation, it is likely that the surgery artificially amplifies monocyte mobilization from the new implanted donor spleen, which could partly explain that 45% of monocytes found in blood 24 h after transplantation derived from the spleen. For instance, the stress of surgery might lead to increased production of circulating AngII [58], which could in turn mobilize Ly6Chigh monocytes from the spleen as we recently reported [28▪,51]. We found that after 3 days of AngII, Ly6Chigh and Ly6Clow monocytes are mobilized from the spleen into the circulation, in agreement with an earlier study [59].

Despite the difficulty in quantifying the exact contribution of the spleen to atherosclerotic plaque growth, the role of the spleen as a monocyte donor is now undeniable. More recent studies suggest that 5–10% of the myeloid cells that accumulate in the aorta come from the spleen [47]. AngII appears to have a crucial function in the splenic hematopoiesis and monocyte mobilization during inflammation.

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A large body of evidence suggests a role for AngII in the proatherogenic process. Activity of the enzymes that generate AngII (i.e., renin and angiotensin-converting enzyme) is associated with increased cardiovascular disease in humans [60,61]. AngII levels are increased in plasma and detected in atherosclerotic plaque macrophages [62]. In mice, AngII delivery accelerates atherosclerosis and aneurysm formation [63]. In addition to its hemodynamic effects [64], Ang II exerts several direct effects on monocyte production and trafficking [65]. AngII alone is sufficient to trigger extramedullary macrophage progenitor amplification, with no effect on bone marrow. Splenocytes from mice infused for 1 week with AngII showed elevated colony-forming unit-macrophage (CFU-M) activity in vitro[49]. AngII also plays a role in HSPC retention in the spleen through repression of S1P1 expression in HSPCs, which dampens their recirculation capacities. Because HSPCs deficient for the AngII receptor, AGTR1A, fail to down-regulate S1P1 in mice, AngII repression effect is thought to require direct signaling through the AGTR1A receptor [49].

Aside from its role in HSPC retention in the spleen, as evoked earlier, we found that AngII promoted monocyte subset release from the spleen after 3 days of infusion in Apoe/ mice, and subsequently promoted abdominal aortic aneurysm formation. AngII delivery to Apoe/ induced a sequential and transitory increase of monocyte subsets in blood concomitant with simultaneous mobilization from the spleen. Classical Ly-6Chigh monocytes peaked at day 3 and waned by day 7, whereas nonclassical Ly-6Clow monocytes increased at day 7 and decreased to normal levels after 14 days [28▪]. This might be accounted for by the conversion of Ly-6Chigh monocytes that were not recruited to the inflamed vessel into Ly-6Clow monocytes (Fig. 1). This sequential kinetics was similar to what was observed in other models of acute injury, indicating that monocytes in the subcapsular red pulp could be rapidly mobilized [66]. Whether AngII accelerates atherosclerosis through mobilization of splenic monocytes is still unclear.

Our recent data suggest that mobilization of monocytes from the spleen may not require direct signals, but rather act through an intermediate partner. We found that ApoE/Rag2/ mice, which lack both T and B cells, are unable to mobilize splenic monocyte in response to AngII. We incriminated B cells as the main partner in this mobilization process as anti-CD20 antibody treatment, which predominantly depletes B2 cells [67,68], completely abrogated AngII-mediated monocyte liberation from the spleen. Monocyte mobilization capacity was restored after transfer of total but not B-cell depleted splenocytes to Apoe/Rag2/ mice [28▪]. This work suggests that AngII primes splenic B cells to guide monocyte egress from the spleen (Fig. 1). This concept of B-cell-driven migration of monocytes is in line with recent findings, showing that mature B cells drive Ly-6Chigh monocytes migration to the infarcted heart [21▪▪]. The precise mechanisms by which splenic B cells promote monocyte mobilization in response to AngII are still unknown, and need to be further investigated.

In addition to their role in monocyte trafficking, lymphocytes may influence HSPC proliferation in the spleen. Together with HSPCs, innate response activator (IRA) B cells from ApoE/ mice on HFD increase their expression of the common β subunit of the GM-CSF/IL-3 receptor and expand [48]. IRA B cells also produce GM-CSF and IL-3 and could therefore drive HSPC proliferation in the spleen [69▪▪]. Whether splenic B cells produce GM-CSF and IL-3 in response to AngII is still an open question. T lymphocytes may also intervene in splenic extramedullary myelopoiesis in ApoE/ mice. FoxP3+ regulatory T cells have been found to negatively regulate the splenic myelopoiesis through the suppression of T cells that produce myelopoietic cytokines in a cell-contact-dependent manner. FoxP3-deficient mice showed increased numbers of GM-CSF+ and IL-3+ T-cells and higher numbers of the CD11b+ GR-1+ myelopoietic cells in the spleen [70].

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Atherosclerosis development mostly depends on hypercholesterolemia and accumulation of inflammatory cells. High cholesterol levels increase the amount of circulating monocytes by activating HSPC proliferation in the medullar and extramedullar compartments, making more monocytes available for recruitment into plaques. The role of the spleen as a reservoir and supplier of monocytes has recently gained considerable interest in the context of atherosclerosis and other CVD settings. Our work, together with the work of others, has brought new mechanistic insights into understanding how and when the spleen deploys additional squads of monocytes. In particular, the role of B-lymphocytes in monitoring monocyte trafficking in and out of the spleen in response to AngII has recently emerged. Further studies are required to elucidate the mechanisms involved in this new pathway. Therapeutic approaches aimed at limiting monocyte-dependent pathogenic activities through modulation of the splenic cellular and molecular components may thus become a promising future direction in the prevention and treatment of CVDs.

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We are grateful to Dr Alain Tedgui for his important contribution to work discussed in this review.

No disclosure of funding to declare.

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Financial support and sponsorship

This work was supported by INSERM grants.

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Conflicts of interest

There are no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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atherosclerosis; migration; monocytes; spleen

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