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 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 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 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.
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.
Alleva DG, Kaser SB, Beller DI. Intrinsic defects in macrophage IL-12 production associated with immune dysfunction in the MRL/++ and New Zealand Black/White F1 lupus-prone mice and the Leishmania major-susceptible BALB/c strain. J Immunol 161(12):6878-6884, 1998.
Anders H-J, Frink M, Linde Y, Banas B, Wörnle M, Cohen CD, Vielhauer V, Nelson PJ, Gröne H-J, Schlöndorff D. CC Chemokine Ligand 5/RANTES Chemokine Antagonists Aggravate Glomerulonephritis Despite Reduction of Glomerular Leukocyte Infiltration. J Immunol 170(11):5658-5666, 2003a.
Anders H-J, Frink M, Linde Y, Banas B, Wörnle M, Cohen CD, Vielhauer V, Nelson PJ, Gröne H-J, Schlöndorff D. CC Chemokine Ligand 5/RANTES Chemokine Antagonists Aggravate Glomerulonephritis Despite Reduction of Glomerular Leukocyte Infiltration. J Immunol 170(11):5658-5666, 2003b.Anders H-J, Ryu M. Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. Kidney Int 80(9):915-925, 2011.
Aprahamian T, Bonegio RG, Richez C, Yasuda K, Chiang L-K, Sato K, Walsh K, Rifkin IR. The peroxisome proliferator-activated receptor gamma agonist rosiglitazone ameliorates murine lupus by induction of adiponectin. J Immunol 182(1):340-346, 2009.
Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 197(6):711-723, 2003.
Bijl M, Reefman E, Horst G, Limburg PC, Kallenberg CGM. Reduced uptake of apoptotic cells by macrophages in systemic lupus erythematosus: correlates with decreased serum levels of complement. Ann Rheum Dis 65(1):57-63, 2006.
Bouhlel MA, Derudas B, Rigamonti E, Dièvart R, Brozek J, Haulon S, Zawadzki C, Jude B, Torpier G, Marx N, Staels B, Chinetti-Gbaguidi G. PPAR[gamma] activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 6(2):137-143, 2007.
Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPAR-[gamma] dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 7(1):48-52, 2001.
Davis TA, Lennon G. Mice with a regenerative wound healing capacity and an SLE autoimmune phenotype contain elevated numbers of circulating and marrow-derived macrophage progenitor cells. Blood Cells Mol Dis 34(1):17-25, 2005.
Fabricius D, Neubauer M, Mandel B, Schütz C, Viardot A, Vollmer A, Jahrsdörfer B, Debatin K-M. Prostaglandin E2 inhibits IFN-α secretion and Th1 costimulation by human plasmacytoid dendritic cells via E-prostanoid 2 and E-prostanoid 4 receptor engagement. J Immunol 184(2):677-684, 2010.
Feig JE, Parathath S, Rong JX, Mick SL, Vengrenyuk Y, Grauer L, Young SG, Fisher EA. Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaques. Circulation 123(9):989-998, 2011.
Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Immunol 13(1):114-119, 2001.
Hagiwara E, Gourley MF, Lee S, Klinman DM. Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10: Interferon-γ-secreting cells in the peripheral blood. Arthritis Rheum 39(3):379-385, 1996.
Jin O, Sun L-Y, Zhou K-X, Zhang X-S, Feng X-B, Mok M-Y, Lau C-S. Lymphocyte apoptosis and macrophage function: correlation with disease activity in systemic lupus erythematosus. Clin Rheumatol 24(2):107-110, 2005.
Kariuki SN, Kirou KA, Macdermott EJ, Barillas-Arias L, Crow MK, Niewold TB. Cutting edge: Autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-α in lupus patients in vivo. J Immunol 182(1):34-38, 2009.
Kavai M, Szegedi G. Immune complex clearance by monocytes and macrophages in systemic lupus erythematosus. Autoimmun. Rev. 6(7):497-502, 2007.
Lee EY, Lee Z-H, Song YW. CXCL10 and autoimmune diseases. Autoimmun Rev 8(5):379-383, 2009.
Lefèvre L, Galès A, Olagnier D, Bernad J, Perez L, Burcelin R, Valentin A, Auwerx J, Pipy B, Coste A. PPARγ ligands switched high fat diet-induced macrophage M2b polarization toward M2a thereby improving intestinal Candida elimination. PLoS One 5(9):e12828, 2010.
Li Y, Lee P, Sobel E, Narain S, Satoh M, Segal M, Reeves W, Richards H. Increased expression of FcgammaRI/CD64 on circulating monocytes parallels ongoing inflammation and nephritis in lupus. Arthritis Res Ther 11(1):R6, 2009.
Liao CH, Yao TC, Chung HT, See LC, Kuo ML, Huang JL. Polymorphisms in the promoter region of RANTES and the regulatory region of monocyte chemoattractant protein-1 among Chinese children with systemic lupus erythematosus. J Rheumatol 31(10):2062-2067, 2004.
Liu J, Beller D. Aberrant production of IL-12 by macrophages from several autoimmune-prone mouse strains is characterized by intrinsic and unique patterns of NF-kappa B expression and binding to the IL-12 p40 promoter. J Immunol 169(1):581-586, 2002.
Llorente L, Richaud-Patin Y, García-Padilla C, Claret E, Jakez-Ocampo J, Cardiel MH, Alcocer-Varela J, Grangeot-Keros L, Alarcón-Segovia D, Wijdenes J, Galanaud P, Emilie D. Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum 43(8):1790-1800, 2000.
Manfredi AA, Rovere P, Galati G, Heltai S, Bozzolo E, Soldini L, Davoust J, Balestrieri G, Tincani A, Sabbadini MG. Apoptotic cell clearance in systemic lupus erythematosus. I. Opsonization by antiphospholipid antibodies. Arthritis Rheum 41(2):205-214, 1998.
Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25(12):677-686, 2004.
Marks SD, Williams SJ, Tullus K, Sebire NJ. Glomerular expression of monocyte chemoattractant protein-1 is predictive of poor renal prognosis in pediatric lupus nephritis. Nephrol Dial Transplant 23(11):3521-3526, 2008.
Menke J, Hsu M-Y, Byrne KT, Lucas JA, Rabacal WA, Croker BP, Zong X-H, Stanley ER, Kelley VR. Sunlight triggers cutaneous lupus through a CSF-1-dependent mechanism in MRL-Fas(lpr) mice. J Immunol 181(10):7367-7379, 2008.
Midgley A, Mclaren Z, Moots RJ, Edwards SW, Beresford MW. The role of neutrophil apoptosis in juvenile-onset systemic lupus erythematosus. Arthritis Rheum 60(8):2390-2401, 2009.
Pawar RD, Patole PS, Zecher D, Segerer S, Kretzler M, Schlondorff D, Anders H-J. Toll-like receptor-7 modulates immune complex glomerulonephritis. J Am Soc Nephrol 17(1):141-149, 2006.
Porta C, Rimoldi M, Raes G, Brys L, Ghezzi P, Di Liberto D, Dieli F, Ghisletti S, Natoli G, De Baetselier P, Mantovani A, Sica A. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor κB. Proc Natl Acad Sci U S A 106(35):14978-14983, 2009.
Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, De Bakker PIW, Le JM, Lee H-S, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 357(10):977-986, 2007.
Roszer T, Menendez-Gutierrez MP, Lefterova MI, Alameda D, Nunez V, Lazar MA, Fischer T, Ricote M. Autoimmune kidney disease and impaired engulfment of apoptotic cells in mice with macrophage peroxisome proliferator-activated receptor gamma or retinoid X receptor alpha deficiency. J Immunol 186(1):621-631, 2011.
Santer DM, Yoshio T, Minota S, Moller T, Elkon KB. Potent induction of IFN-alpha and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus. J Immunol 182(2):1192-1201, 2009.
Schiffer L, Bethunaickan R, Ramanujam M, Huang W, Schiffer M, Tao H, Madaio MP, Bottinger EP, Davidson A. Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. J Immunol 180(3):1938-1947, 2008.
Schindler H, Lutz MB, Röllinghoff M, Bogdan C. The production of IFN-γ by IL-12/IL-18-activated macrophages requires STAT4 signaling and is inhibited by IL-4. J Immunol 166(5):3075-3082, 2001.
Serezani CH, Lewis C, Jancar S, Peters-Golden M. Leukotriene B4 amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression. J Clin Invest 121(2):671-682, 2011.
Sharif MN, Tassiulas I, Hu Y, Mecklenbrauker I, Tarakhovsky A, Ivashkiv LB. IFN-alpha priming results in a gain of proinflammatory function by IL-10: implications for systemic lupus erythematosus pathogenesis. J Immunol 172(10):6476-6481, 2004.
Shirakawa F, Yamashita U, Suzuki H. Reduced function of HLA-DR-positive monocytes in patients with systemic lupus erythematosus (SLE). J Clin Immunol 5(6):396-403, 1985.
Shome GP, Yamane K. Decreased release of leukotriene B4 from monocytes and polymorphonuclear leukocytes in patients with systemic lupus erythematosus. Allergy 40(1):72-81, 1991.
Sigurdsson S, Nordmark G, Garnier S, Grundberg E, Kwan T, Nilsson O, Eloranta M-L, Gunnarsson I, Svenungsson E, Sturfelt G, Bengtsson AA, Jönsen A, Truedsson L, Rantapää-Dahlqvist S, Eriksson C, Alm G, Göring HHH, Pastinen T, Syvänen A-C, Rönnblom L. A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5. Hum Mol Genet 17(18):2868-2876, 2008.
Spurney RF, Ruiz P, Pisetsky DS, Coffman TM. Enhanced renal leukotriene production in murine lupus: Role of lipoxygenase metabolites. Kidney Int 39(1):95-102, 1991.
Steinbach F, Henke F, Krause B, Thiele B, Burmester G-R, Hiepe F. Monocytes from systemic lupus erythematous patients are severely altered in phenotype and lineage flexibility. Ann Rheum Dis 59(4):283-288, 2000.
Sui M, Zhou J, Jia X, Mu S, Liu X, Ji Y, Xie R. Expression and significance of CD80/CD86 in renal tissue of lupus nephritis. Chin J Int Med 49(8):691-695, 2010.
Triantafyllopoulou A, Franzke C-W, Seshan SV, Perino G, Kalliolias GD, Ramanujam M, Van Rooijen N, Davidson A, Ivashkiv LB. Proliferative lesions and metalloproteinase activity in murine lupus nephritis mediated by type I interferons and macrophages. Proc Natl Acad Sci U S A 107(7):3012-3017, 2010.
Venegas-Pont M, Sartori-Valinotti JC, Maric C, Racusen LC, Glover PH, Mclemore GR, Jr., Jones AV, Reckelhoff JF, Ryan MJ. Rosiglitazone decreases blood pressure and renal injury in a female mouse model of systemic lupus erythematosus. Am J Physiol 296:R1282-R1289, 2009.
Viallard, Pellegrin, Ranchin, Schaeverbeke, Dehais, Longy B, Ragnaud, Leng, Moreau. Th1 (IL-2, interferon-gamma (IFN-γ)) and Th2 (IL-10, IL-4) cytokine production by peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE). Clin Exp Immunol 115(1):189-195, 1999.
Wagrowska-Danilewicz M, Stasikowska O, Danilewicz M. Correlative insights into immunoexpression of monocyte chemoattractant protein-1, transforming growth factor beta-1 and CD68+ cells in lupus nephritis. Pol J Pathol 56(3):115-120, 2005.
Wang L, Erling P, Bengtsson AA, Truedsson L, Sturfelt G, Erlinge D. Transcriptional down-regulation of the platelet ADP receptor P2Y12 and clusterin in patients with systemic lupus erythematosus. J Thromb Haemost 2(8):1436-1442, 2004.
Wang Y, Wang YP, Zheng G, Lee VWS, Ouyang L, Chang DHH, Mahajan D, Coombs J, Wang YM, Alexander SI, Harris DCH. Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. Kidney Int 72(3):290-299, 2007.
Wermeling F, Chen Y, Pikkarainen T, Scheynius A, Winqvist O, Izui S, Ravetch JV, Tryggvason K, Karlsson MCI. Class A scavenger receptors regulate tolerance against apoptotic cells, and autoantibodies against these receptors are predictive of systemic lupus. J Exp Med 204(10):2259-2265, 2007.
Yu C, Sun K, Tsai C, Tsai Y, Tsai S, Huang D, Han S, Yu H. Expression of Th1/Th2 cytokine mRNA in peritoneal exudative polymorphonuclear neutrophils and their effects on mononuclear cell Th1/Th2 cytokine production in MRL-lpr/lpr mice. Immunology 95(3):480-487, 1998.
Zhang W, Xu W, Xiong S. Blockade of Notch1 signaling alleviates murine lupus via blunting macrophage activation and M2b polarization. J Immunol 184(11):6465-6478, 2010.
Zhao W, Thacker SG, Hodgin JB, Zhang H, Wang JH, Park JL, Randolph A, Somers EC, Pennathur S, Kretzler M, Brosius FC, 3rd, Kaplan MJ. The peroxisome proliferator-activated receptor gamma agonist pioglitazone improves cardiometabolic risk and renal inflammation in murine lupus. J Immunol 183:2729-2740, 2009.
Zheng L, Sinniah R, Hsu S. In situ glomerular expression of activated NF-kappaB in human lupus nephritis and other non-proliferative proteinuric glomerulopathy. Virchows Arch 448(2):172-183, 2006.
Zorro Manrique S, Duque Correa MA, Hoelzinger DB, Dominguez AL, Mirza N, Lin H-H, Stein-Streilein J, Gordon S, Lustgarten J. Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth. J Exp Med 208(7):1485-1499, 2011.
[Discovery Medicine; ISSN: 1539-6509; Discov Med 13(69):151-158, February 2012. Copyright © Discovery Medicine. All rights reserved.]