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Link to original content: https://doi.org/10.1172/JCI30992
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Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
Address correspondence to: Siamon Gordon, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX13RE, United Kingdom. Phone: 44-1865-275534; Fax: 44-1865-275515; E-mail: siamon.gordon@path.ox.ac.ukor christine.holt@path.ox.ac.uk.
Find articles by Gordon, S. in: JCI | PubMed | Google Scholar
Published January 2, 2007 - More info
Monocytes participate critically in atherosclerosis. There are 2 major subsets expressing different chemokine receptor patterns: CCR2+CX3CR1+Ly-6Chi and CCR2–CX3CR1++Ly-6Clo monocytes. Both C-C motif chemokine receptor 2 (CCR2) and C-X3-C motif chemokine receptor 1 (CX3CR1) are linked to progression of atherosclerotic plaques. Here, we analyzed mouse monocyte subsets in apoE-deficient mice and traced their differentiation and chemokine receptor usage as they accumulated within atherosclerotic plaques. Blood monocyte counts were elevated in apoE–/– mice and skewed toward an increased frequency of CCR2+Ly-6Chi monocytes in apoE–/– mice fed a high-fat diet. CCR2+Ly-6Chi monocytes efficiently accumulated in plaques, whereas CCR2–Ly-6Clo monocytes entered less frequently but were more prone to developing into plaque cells expressing the dendritic cell–associated marker CD11c, indicating that phagocyte heterogeneity in plaques is linked to distinct types of entering monocytes. CCR2– monocytes did not rely on CX3CR1 to enter plaques. Instead, they were partially dependent upon CCR5, which they selectively upregulated in apoE–/– mice. By comparison, CCR2+Ly-6Chi monocytes unexpectedly required CX3CR1 in addition to CCR2 and CCR5 to accumulate within plaques. In many other inflammatory settings, these monocytes utilize CCR2, but not CX3CR1, for trafficking. Thus, antagonizing CX3CR1 may be effective therapeutically in ameliorating CCR2+ monocyte recruitment to plaques without impairing their CCR2-dependent responses to inflammation overall.
Frank Tacke, David Alvarez, Theodore J. Kaplan, Claudia Jakubzick, Rainer Spanbroek, Jaime Llodra, Alexandre Garin, Jianhua Liu, Matthias Mack, Nico van Rooijen, Sergio A. Lira, Andreas J. Habenicht, Gwendalyn J. Randolph
Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80+CD11c+ population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or “alternatively activated” macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-α and iNOS that are characteristic of M1 or “classically activated” macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2–KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-α–induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.
Carey N. Lumeng, Jennifer L. Bodzin, Alan R. Saltiel
Macrophage accumulation participates decisively in the development and exacerbation of atherosclerosis. Circulating monocytes, the precursors of macrophages, display heterogeneity in mice and humans, but their relative contribution to atherogenesis remains unknown. We report here that the Ly-6Chi monocyte subset increased dramatically in hypercholesterolemic apoE–deficient mice consuming a high-fat diet, with the number of Ly-6Chi cells doubling in the blood every month. Ly-6Chi monocytes adhered to activated endothelium, infiltrated lesions, and became lesional macrophages. Hypercholesterolemia-associated monocytosis (HAM) developed from increased survival, continued cell proliferation, and impaired Ly-6Chi to Ly-6Clo conversion and subsided upon statin-induced cholesterol reduction. Conversely, the number of Ly-6Clo cells remained unaffected. Thus, we believe that Ly-6Chi monocytes represent a newly recognized component of the inflammatory response in experimental atherosclerosis.
Filip K. Swirski, Peter Libby, Elena Aikawa, Pilar Alcaide, F. William Luscinskas, Ralph Weissleder, Mikael J. Pittet
Monocytes and mature macrophages are prominent in the host response to lipid accumulation in major arteries, the development of atherosclerotic plaques, and their complications (1). Less established are the details of their colocalization and possible metabolic interactions with adipocytes in body fat stores (2). New studies reported in this issue of the JCI by Swirski et al. (3) demonstrate that a monocyte subset that expresses high levels of a marker antigen, Ly-6C, dominates hypercholesterolemia-associated monocytosis and gives rise to macrophages in atheromata. Also in this issue, Tacke et al. (4) report that monocyte subsets differentially employ the chemokine receptors C-C motif chemokine receptor 2 (CCR2), CCR5, and C-X3-C motif chemokine receptor 1 (CX3CR1, also known as the fractalkine receptor) to enter atherosclerotic plaques. They also exploited an mAb, Gr-1, directed against Ly-6 family antigens to distinguish monocyte subsets and used CD11c, a β2 integrin expressed by myeloid DCs and selected tissue macrophages, to characterize the phenotype of macrophage subpopulations in lesions. In the third of this trio of articles, Lumeng et al. (5), by contrast, document that adipose tissue macrophages, which accumulate with obesity and are implicated in insulin resistance, switch their phenotype from one of an alternatively activated (M2) polarization to proinflammatory (M1) cells and that a subset of these cells expresses elevated levels of the CD11c marker. Collectively, these studies extend our knowledge of heterogeneity of monocyte recruitment and the macrophage phenotype in response to different inflammatory and metabolic stimuli and reinforce the importance of macrophage interactions with adipocytes, as well as with endothelium, smooth muscle, and other cells in the lipid-rich tissue microenvironment.
Lipid-laden macrophages, known as foam cells, play a central role in the pathogenesis and repair of atherosclerotic plaques, the product of local cellular inflammatory reactions in arterial walls (6). Macrophages have also been implicated in plaque vulnerability to rupture and thrombus formation. Their recruitment depends on circulating monocyte levels and is greatly reduced in M-CSF–deficient osteopetrotic mice, which display a variable deficiency of tissue macrophage populations in the absence of this important growth and survival factor (7). Recently, interest has grown in the observations by several groups that circulatory monocytes express distinctive chemokine receptors, particularly with respect to CX3CR1 and CCR2 (also known as receptor for monocyte chemoattractant protein 1 [MCP-1]), as well as antigen markers such as Gr-1; CD14, a receptor for LPS-binding protein; and CD16, an Fc receptor (8, 9). Figure 1 summarizes the present consensus that different monocyte subsets give rise to constitutively present, resident macrophages and to tissue macrophages that have been recruited in increased numbers to local sites of infection and immunologic injury. There is evidence that this distinctive recruitment property of CD14+CD16+, which is not present in CD14++CD16– monocytes, mediated by CX3CR1hiCCR2–CD62 ligand– (CX3CR1hiCCR2–CD62L–) and CX3CR1loCCR2+CD62L+ subpopulations, respectively, is conserved in several species, including mice and humans. While the origin of microbially elicited, acute inflammatory macrophages is more readily demonstrable experimentally, the sources of resident tissue macrophages, which turn over more slowly, are less clear. The origins of nonclassical inflammatory macrophages elicited by metabolic stimuli, such as modified (lipo)proteins in atherosclerosis, diabetes mellitus, and Alzheimer disease, have not been hitherto characterized.
Figure 1Heterogeneity of monocytes and tissue macrophages. This schematic summarizes previous evidence for monocytic subsets giving rise to tissue macrophages and myeloid DCs in the absence and presence of microbially elicited inflammation. Two distinct subpopulations of monocytes can be identified in the circulation, CD14+CD16+ versus CD14++CD16– in the human and Ly-6lo/Gr-1lo versus Ly-6hi/Gr-1hi in the mouse. There are also differences in expression of CX3CR1 (fractalkine receptor), CCR2, and CD62L (L selectin ligand). Experimental studies in rodents have shown that the CX3CR1lo subset gives rise to recruited macrophages and DCs, in response to a proinflammatory stimulus, whereas the CX3CR1lo subset may give rise to resident tissue cells.
Once present in tissues, mature macrophages exhibit another level of heterogeneity. Microbial stimuli acting through a variety of TLRs and non-TLRs, such as dectin-1, induce a range of transcriptional and nontranscriptional effector responses (known as innate activation) (9, 10). The cytokine IFN-γ induces a signature of proinflammatory antimicrobial activities (known as classical activation) that are important in cell-mediated immunity to intracellular pathogens and are associated with Th1 lymphocyte responses. A distinctive, “alternative activation” profile is associated with Th2-type polarized responses. Characteristic features of IL-4– and IL-13–induced (M2) phenotypes include enhanced MHC class II expression, as in IFN-γ–induced M1 macrophages, but distinctive upregulation of endocytic lectin-like receptors (e.g., the mannose receptor) and of arginase, rather than inducible NOS2 (Table 1). Alternative activation is strongly associated with extracellular parasitic infections, allergy, humoral immunity, and fibrosis. Macrophage deactivation is equally complex and characterized by distinctive, partially overlapping signatures of gene expression induced by IL-10, glucocorticoids, TGF-β, and other regulatory mediators.
A further level of heterogeneity to consider relates to the origin, differentiation, and activation of myeloid DCs (11). These cells arise from common progenitors and share many phenotypic characteristics with macrophages, namely phagocytosis, receptor expression, and cytokine secretion, but acquire a unique antigen-presenting capacity for naive T lymphocytes as they undergo a complex process of maturation. They become actively migratory cells, responding to selected chemokines as they deliver antigen to draining lymph nodes. However, DCs display considerable heterogeneity in lymphoid and nonlymphoid tissues, which has been difficult to establish in situ, rather than in the simpler in vitro model systems that are widely employed, and they express many apparently selective markers, such as CD11c, also expressed by tissue macrophages.
These intriguing studies have yielded further insights into the complexity of monocytes and tissue macrophages and the role of different chemokine receptors in constitutive and lipid-induced recruitment (summarized in Figure 2). It is clear that enhanced recruitment induced by metabolic and infectious inflammatory stimuli differs in important aspects that need better definition, in view of their importance in modified, often chronic inflammatory disease processes such as diabetes, as well as atherosclerosis. The nature of monocyte/macrophage heterogeneity is also difficult to assess due to the considerable plasticity of macrophages, their repertoire of receptors and extensive biosynthetic capacity. Furthermore, it is important not to overinterpret the expression of a single marker, such as CD11c, as indicative of DC differentiation. A panel of markers should be investigated, in situ if possible, and even then in relation to the complexity of macrophage differentiation and modulation in different tissue microenvironments. As to possible therapeutic exploitation, further investigation is required before different subsets of cells can be selectively, efficiently, and safely targeted. The availability of well-characterized experimental mouse models, as described in the articles under discussion, makes this an attractive goal. Their possible relevance to human disease poses further challenges for pathophysiological, translational research.
Figure 2Monocyte and macrophage recruitment and response to tissue lipids. Summary of findings reported in the present studies (3–5). It is not clear whether individual monocytes express all markers and whether cells of each subset are recruited stochastically from the circulation. Some markers are not shown, which reflects lack of study rather than absence of expression. See text for role of Gr-1lo cells in atherosclerosis and in the generation of CD11c– cells. CCR5 involvement is partial (part; see text).
