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February 23, 2012

Macrophage Subpopulations in Systemic Lupus Erythematosus

Posted in: Adaptive Immunity, Autoimmune Disease, Autoimmunity, CD4 T Cell, Chronic Inflammation, Lupus Nephritis, Macrophage, Rosiglitazone, Systemic Lupus Erythematosus, T Cell, Thiazolidinedione, Type 1 T Helper Cell, Type 2 T Helper Cell


Systemic lupus erythematosus (SLE) is a heterogeneous group of autoimmune disorders defined by a consensus of clinical and laboratory criteria. Much of the pathophysiology and therapy of SLE has focused on autoimmune B and T cells of the adaptive immune system. Recently, focus has shifted to the role of macrophages — part of the innate immune system — in SLE pathogenesis.

Scientists’ view of macrophages has changed significantly in the past decade. What was once considered a monolithic group of waste collectors is now a heterotypic, heterogeneous population of multipurpose cells. In much the same way as effector T cells have been parsed and scrutinized for their diversity, macrophages are now being subdivided and classified anew. These new classes have important and increasingly relevant roles in a number of disease states. However, the new nomenclature has yet to be used to study macrophage pathogenesis specific to SLE. In this review, we first give an overview of the latest macrophage nomenclature. We further discuss, per observations in the literature, the roles of various macrophage subtypes in the pathogenesis of SLE based on our current understanding of the disease.

Macrophage Subtypes Have Varying Roles

In the last several years, macrophages have been increasingly subdivided and categorized based on apparent activity, location, and cell surface marker expression. One of the most useful classifications to emerge has been that of Mantovani et al. (2004) which subdivides activated macrophages into M1, M2a, M2b, and M2c subtypes (Table 1). Other subdivision methods as cited in the table help to round out a subpopulation-based view of macrophage classification.

These subdivisions can make reversible changes that respond to the micro-environmental milieu. While they do not necessarily represent distinct populations of cells, they do represent a useful functional nomenclature by which broad insights may be made into their function in disease.

As of yet, little work has been done to establish what the individual role of these macrophage subtypes might be in SLE pathogenesis. We undertake here a review of possible macrophage subtype contributions to disease based on current leads.

M1 Mayhem — The Runaway M1 Hypothesis Explains Some SLE Pathology

Type 1 versus type 2 immune responses

A useful and dominant nomenclature for CD4+ T cells reflects the roles that these helper cells play in a given scenario of inflammation. Type 1 immune response, mediated by TH1 cells, refers to the inflammatory response that clears viral, bacterial, and protozoan infections. Type 2 immune response, mediated by TH2 cells, refers to a response that is more efficacious in clearing parasites. This classification has been extraordinarily useful in the systematic study of the adaptive immune response, and it has grown to include other subsets of helper T cells.

Not surprisingly, helper T cells are not the only player in any given immune response. It has since been discovered that distinct populations of macrophages, termed M1 and M2 cells, facilitate and control type 1 and type 2 immune responses, respectively. Just as TH1 cells facilitate inflammation and help clear typical pathogens, M1 macrophages are pro-inflammatory and assist in controlling infections by expressing reactive oxygen species (ROS), complement and immunoglobulin receptors, and inflammatory cytokines. On the other hand, M2 macrophages express a different set of cytokines that appears related to type 2 immune responses and anti-inflammatory processes.

SLE is a markedly inflammatory disease in the absence of appropriate pathogens. One important theory in the pathogenesis of SLE is that inflammatory M1 macrophages could be out of control. An imbalance of M1 over M2 may explain the runaway inflammation that is an essential feature of SLE.

Evidence for the M1 dominance hypothesis

M1 macrophages are classical phagocytic, inflammatory macrophages that act in delayed-type (type IV) hypersensitivities, tumor resistance, and type 1 inflammation. They have long been believed to be a source of pathology in SLE. Several markers of M1 macrophages are elevated in SLE macrophages, as highlighted in Table 1. These include CD86 (Sui et al., 2010), which correlates with the severity of renal pathology; IFN-γ (Jin et al., 2005), IL-6 (Hagiwara et al., 1996), CCL2 (Li et al., 2009), and CXCL10 from circulating macrophages (Lee et al., 2009); CXCL10 from neurological lupus macrophages (Santer et al., 2009); and CCL2 from intrarenal macrophages (Marks et al., 2008; Wagrowska-Danilewicz et al., 2005). These markers are important in macrophage activation state, chemotaxis, and general pro-inflammatory activity.

M1 macrophages are also favored by the milieu they reside in. SLE serum contains large amounts of TNF-α (Bennett et al., 2003), GM-CSF (Midgley et al., 2009), and IFN-γ (Bennett et al., 2003), each of which contributes to type 1 inflammation propagation. TNF-α is a particularly potent M1 cytokine that is known to change the ways in which macrophages respond to their environment. It is one of the “danger signals” described by Gallucci and Matzinger (2001) that fundamentally alters macrophage cell signaling calculus.

Predisposing genetic factors also support the M1 dominance hypothesis. IFN-γ production by M1 cells utilizes the STAT4 pathway and is inhibited by factors predisposing to the M2a phenotype (Schindler et al., 2001). STAT4 polymorphisms have been linked intimately with SLE (Remmers et al., 2007; Sigurdsson et al., 2008) and appear to increase M1 sensitivity to cytokines in these patients (Kariuki et al., 2009). Circulating CSF-1, which is elevated in SLE patient serum, appears to induce a Ly6Chigh M1 phenotype. Cutaneous manifestations of lupus in MRL-lpr mice exposed to sunlight are also mediated by CSF-1 (Menke et al., 2008) and are therefore probably M1-mediated. Indeed, recent work in models of atherosclerosis — which occurs frequently in patients with SLE — showed the importance of the M1 subtype in instigating inflammation as well as M2 macrophages in reducing it (Feig et al., 2011). While HMG-CoA reductase inhibitors may be expected to have multiple unrelated effects, they have also been shown to improve lupus symptoms by unknown mechanisms (van Leuven et al., 2011).

M1 versus M2 as an insufficient paradigm

The M1 versus M2 paradigm may represent an oversimplification of the inflammation in SLE. M1 macrophages are unlikely to produce the large amounts of IL-10 seen in SLE (Hagiwara et al., 1996; Viallard et al., 1999); this expression pattern is a hallmark of all M2 subtypes (Mantovani et al., 2004). Immune complexes and other Toll-like receptor (TLR) agonists, which are abundant in SLE serum, are further expected to favor the M2b subtype. M2b macrophages secrete IL-6 that is elevated in peripheral SLE macrophages (Hagiwara et al., 1996) and the subtype has been induced in mouse macrophages using anti-dsDNA antibodies (Jang et al., 2009). Further, CCL5 antagonists, which might be expected to blunt renal injury because they block M1 actions on cytotoxic T and NK cells, actually accentuate mouse models of renal damage even in the absence of lymphocyte infiltration (Anders et al., 2003b). These findings paint a more nuanced picture of macrophage subpopulation contribution to SLE. A recent review by Anders and Ryu (2011) suggested that increased M1 as well as M2 macrophage subpopulations in various kidney pathologies could explain various findings and influence disease course.

M2 Subpopulations also Contribute to SLE Pathology

M2 macrophages are generally divided into a, b, and c subtypes. They appear to perform separate tasks in inflammation and are designated by different monikers in different publications. M2a macrophages are referred to as alternatively activated or profibrotic; M2b as regulator or TH2-related; and M2c as deactivated, remodeling, or anti-inflammatory. Each may have its own role in the pathology of SLE. As discussed above, all M2 macrophages produce an IL-10:IL-12 ratio opposite of M1 macrophages (Mantovani et al., 2004) that is found on both peripheral and renal SLE macrophages (Alleva et al., 1998; Hagiwara et al., 1996; Liu and Beller, 2002; Triantafyllopoulou et al., 2010; Viallard et al., 1999; Yu et al., 1998).

M2a macrophages

M2a macrophages have been characterized as profibrotic (Anders and Ryu, 2011). Fibrosis is a common finding in lupus and has been attributed to macrophage function (Davis and Lennon, 2005), though not definitively attributed to any particular macrophage subpopulation.

M2a macrophages do not appear to be a major macrophage subpopulation in SLE. While data only exists for a few M2a markers, the expression of these markers uniformly decreased in human SLE peripheral macrophages, as highlighted in Table 1. These are MHC II (Shirakawa et al., 1985; Steinbach et al., 2000), MSR1 (CD204) type A scavenger receptor (Wermeling et al., 2007), mannose receptor (Kavai and Szegedi, 2007), and possibly P2Y12 (Wang et al., 2004).

Deliberate expansion of M2a macrophages is one promising therapeutic approach. PPARγ agonists that induce M2a phenotypes in human macrophages (Bouhlel et al., 2007) have shown some promise in mouse tests (Zhao et al., 2009). Further, IL-4 and IL-13-induced macrophages transplanted to adriamycin-induced nephritic SCID mice ameliorates renal disease (Wang et al., 2007).

Further studies on the expression of other important M2a-related markers, including FCεR (CD23) and various lectins, may help elucidate whether there is a dearth of M2a macrophages that might promote SLE progression.

M2b macrophages

M2b macrophages are considered an immunity-regulating macrophage subtype that is associated with SLE and activated by immune complexes. In an activated lymphocyte-derived DNA (ALD-DNA) induced mouse model of lupus, Zhang et al. (2010) showed that increased Notch-1 signaling caused M2b macrophage differentiation. The Notch-1 signaling further caused a lupus-like phenotype. NF-κB p50 is an important part of M2 macrophage differentiation (Porta et al., 2009) and has been shown to be increased in expression in kidneys of SLE patients with glomerulonephritis (Zheng et al., 2006).

SLE serum samples are characterized by an increased ratio of IL-10 to IFNγ secretion (Hagiwara et al., 1996), which could be a direct result of M2b activation. Indeed the surplus of unphagocytosed immune complexes (ICs) that occur in SLE are known to be inducers of M2b macrophages. TLR signaling is also important in renal pathology (Pawar et al., 2006). M2b macrophages are known to produce nonspecific inflammatory factors that are elevated in peripheral SLE macrophages. These include IL-10 (Hagiwara et al., 1996; Viallard et al., 1999), TNF-α (Manfredi et al., 1998; Steinbach et al., 2000), and IL-6 (Hagiwara et al., 1996), as summarized in Table 1.

PPARγ knockout mice, an SLE model, develop high serum anti-nuclear antibody (ANA) and a glomerulonephritis syndrome that is similar to human SLE (Roszer et al., 2011). The M2b macrophage phenotype predominates in these mice and has deficiencies in phagocytosis and apoptotic cell clearance. The use of a PPARγ agonist rosiglitazone has been proposed to divert macrophage differentiation toward the M2a subtype from M2b (Bouhlel et al., 2007; Lefèvre et al., 2010). Rosiglitazone (Venegas-Pont et al., 2009) and pioglitazone (Zhao et al., 2009) have shown short-term therapeutic efficacy in murine lupus nephritis, though the mechanism is not known. With the comorbidity of atherosclerosis and type 2 diabetes with SLE, PPARγ activation is also expected to relieve disease by other mechanisms through adiponectin (Aprahamian et al., 2009). Separately, thiazolidinediones have been shown to be anti-inflammatory independent of PPARγ modulation (Chawla et al., 2001). Macrophage subtype is clearly an important phenomenon, because M2b macrophage levels have been shown to directly correlate with relapse (increasing and stimulating autoimmune response) and remission (decreasing along with a lower autoimmune response) in murine lupus nephritis (Schiffer et al., 2008). This same study showed a dearth of M1 cells in active disease in murine lupus.

Further explorations of NF-κB signaling relating to SLE include the generation of cell-penetrating anti-dsDNA antibodies by Jang et al. (2009). These antibodies were found to induce TNF-α production and, in two cases, activate the NF-κB pathway in RAW264.7 mouse macrophages. Such an induction in a patient with SLE might be expected to drive macrophages toward the M2b phenotype. Paracrine LTB4 appears to amplify the NF-κB and STAT1 transcriptional pathways (Serezani et al., 2011). Both pathways contribute to lymphocyte survival and an inflammatory cytokine milieu. While SLE macrophages produce little LTB4 (Shome and Yamane, 1991), it appears that other cells produce copious amounts of it in lupus nephritis (Spurney et al., 1991).

M2c macrophages

M2c macrophages are alternatively designated deactivated, remodeling, or anti-inflammatory macrophages. This subtype reflects the various roles that M2c phenotype macrophages are thought to play in the immune system.

Interesting findings regarding M2c macrophages in lupus include the fact that serum antibodies against scavenger receptors — expressed largely on the M2c subtype — tend to worsen SLE (Wermeling et al., 2007). Further, CD14 levels, enriched on the M2c subtype, are low on peripheral monocytes and macrophages isolated from patients with SLE (Bijl et al., 2006; Steinbach et al., 2000). Taken together, these might be seen as evidence of a reduction of M2c macrophages in SLE, as summarized in Table 1.

One promising role of M2c macrophages is their reputed anti-inflammatory effect. High IL-10 levels seen in SLE might normally be expected to lead to M2c macrophage phenotype and a reining in of inflammation. However, high level of type 1 IFN production in SLE (Liao et al., 2004) has been shown to change the ways in which macrophages respond to IL-10 (Sharif et al., 2004). In fact, IL-10 becomes inflammatory in SLE, as evidenced by improvement in human SLE trials with IL-10-blocking antibodies (Llorente et al., 2000). Some postulate that the loss of this subtype contributes greatly to autoimmunity. Indeed, the efficacy of glucocorticoid therapy may be partially due to M2c upregulation.

M2c macrophages also play a role in matrix deposition and tissue remodeling. TGF-β and IL-10, each increased in both peripheral and renal SLE macrophages (Hagiwara et al., 1996; Viallard et al., 1999; Wagrowska-Danilewicz et al., 2005), lead to this phenotype. How their absence or presence might contribute to SLE pathology in this way has yet to be intensively studied. MRL mice show wound healing without fibrosis (Davis and Lennon, 2005). Perhaps this is due to a lack of M2c macrophages in the model.

Regulatory Macrophages (Mregs) May Be Part of the Equation

Long the subject of speculation, regulatory macrophages, termed Mac-regs or Mregs, have now been shown to exist (Zorro Manrique et al., 2011). Mregs express Foxp3, a canonical regulatory T cell transcriptional regulator, and repress inflammation much like their regulatory T cell counterparts. These Mregs further secrete large amounts of PGE2, consistent with a finding in several mouse lupus models (Chae et al., 2008). PGE2 inhibits M1 cell activity (Fabricius et al., 2010) and appears to be a major regulatory mechanism. They further secrete PDGF, which has been shown to be increased on macrophages from polycytidylic acid-accelerated lupus in BWF1 mice (Triantafyllopoulou et al., 2010). It has yet to be proved whether Mregs represent a distinct population from M2c macrophages, as a number of similarities exist.


Macrophage taxonomy is an attempt to rationally categorize an extended variety of cell functions. In that sense, the number of potential macrophage subdivisions is limited only by cell products, chromophores, and flow cytometry parameters. Similarly, macrophage phenotypes are fluid and reversible, unlike committed cell differentiations of pluripotent progenitor cells. The above classifications are likely to overlap, blur, and even bend in the face of disease processes like SLE and in normal physiology. Nevertheless, these classifications offer good starting points to consider potential mechanisms for macrophage contribution to disease.

It appears that the runaway M1 hypothesis has some validity, though it cannot explain all pathological features of SLE driven by macrophages. M2a and M2c populations appear to be reduced and fail to quell the inflammatory activity of M1 as well as other immune cells. On the other hand, M2b may itself contribute to pathology.

These findings suggest several therapeutic targets for treating SLE. By selectively inhibiting the activity of M1 and M2b macrophages, their pro-inflammatory effects may be averted. Anti-interferon, anti-TNF, or anti-growth factor treatments may help limit M1 differentiation. PPARγ agonists, already promising in mouse studies, may serve a dual role in depleting M2b macrophages and stimulating M2a expansion. Boosting M2a, M2c, or Mreg macrophages could help limit inflammation and control disease. As mentioned earlier, glucocorticoids may be partially effective by their positive effect on M2c expansion. However, caution is warranted, as CCL5 antagonists have actually been shown to aggravate kidney disease (Anders et al., 2003a).

Further research may help to better elucidate the contributions of macrophages to SLE. More flow cytometric data comparing markers of healthy and SLE macrophages could facilitate this effort, as aggregated on SLE BASE (www.slebase.org). The development of a consensus of macrophage subpopulation nomenclature may also assist in simplifying the process.


The authors report no conflicts of interest.

Corresponding Author

Chandra Mohan, M.D., Ph.D., Department of Internal Medicine Division of Rheumatology, University of Texas Southwestern Medical Center, Mail Code 8884, Y8.212, 5323 Harry Hines Blvd., Dallas, Texas 75390, USA.


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[Discovery Medicine; ISSN: 1539-6509; Discov Med 13(69):151-158, February 2012. Copyright © Discovery Medicine. All rights reserved.]

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