Logo of arthrestherBioMed Centralbiomed central web sitesearchsubmit a manuscriptregisterthis articleArthritis Research & Therapy
Arthritis Res Ther. 2007; 9(6): 224.
Published online Dec 21, 2007. doi:  10.1186/ar2333
PMCID: PMC2246244

Cells of the synovium in rheumatoid arthritis. Macrophages

Abstract

The multitude and abundance of macrophage-derived mediators in rheumatoid arthritis and their paracrine/autocrine effects identify macrophages as local and systemic amplifiers of disease. Although uncovering the etiology of rheumatoid arthritis remains the ultimate means to silence the pathogenetic process, efforts in understanding how activated macrophages influence disease have led to optimization strategies to selectively target macrophages by agents tailored to specific features of macrophage activation. This approach has two advantages: (a) striking the cell population that mediates/amplifies most of the irreversible tissue destruction and (b) sparing other cells that have no (or only marginal) effects on joint damage.

Introduction

Macrophages (M[var phi]) are of central importance in rheumatoid arthritis (RA) due to their prominent numbers in the inflamed synovial membrane and at the cartilage-pannus junction, their clear activation status [1,2] (see Table Table11 for overview), and their response to successful anti-rheumatic treatment [3]. Although M[var phi] probably do not occupy a causal pathogenetic position in RA (except for their potential antigen-presenting capacity), they possess broad pro-inflammatory, destructive, and remodelling potential and contribute considerably to inflammation and joint destruction in acute and chronic RA. Also, activation of this lineage extends to circulating monocytes and other cells of the mononuclear phagocyte system (MPS), including bone marrow precursors of the myelomonocytic lineage and osteoclasts [2,4,5].

Table 1
Activation status of synovial macrophages and/or circulating monocytes in rheumatoid arthritis

Thus, before a causal factor for RA is known, monocytes/M[var phi] remain an attractive research focus for the following reasons: (a) the radiological progression of joint destruction correlates with the degree of synovial M[var phi] infiltration [1], (b) the therapeutic efficacy of conventional anti-rheumatic therapy coincides with downregulation of MPS functions [6], (c) therapies directed at cytokines made predominantly by M[var phi] are effective in RA [7], (d) conventional or experimental drugs can be selectively targeted to M[var phi] or their different subcellular compartments (for example, [2,8]), (e) differential activation of intracellular signal transduction pathways underlies different M[var phi] effector functions [9], and (f) more specific inhibitors of key metabolic enzymes or particular signal transduction pathways may become available as selective targets of anti-rheumatic therapy [9,10]. In addition, the amplifying role of M[var phi] in RA has emerged so clearly that the effects of anti-rheumatic therapy (whether specific or conventional) on monocytes/M[var phi] may become an objective readout of the effectiveness of treatment [11-13] (Stuhlmuller B, Hernandez MM, Haeupl T, Kuban RJ, Gruetzkau A, Voss JW, Salfeld J, Kinne RW, Burmester GR, unpublished data).

Differentiation and activation of the mononuclear phagocyte system in rheumatoid arthritis

Cells of the myelomonocytic lineage differentiate into several cell types critically involved in disease (that is, monocytes/M[var phi], osteoclasts, and dendritic cells) (Figure (Figure1a).1a). Due to their marked plasticity, these pathways can be influenced by an excess/imbalance of cytokines or growth factors, resulting in altered differentiation/maturation (Figure (Figure1b).1b). In RA, such imbalances clearly occur in inflamed joints, peripheral blood, and bone marrow (Table (Table22 and Figure Figure1b1b).

Figure 1
Physiological/pathological differentiation of the mononuclear phagocyte system in rheumatoid arthritis (RA). (a) Physiological differentiation of the mononuclear phagocyte system (MPS) (steady-state cytokine and growth factor milieu). In the human MPS, ...
Table 2
Potential sites of myelomonocytic activation in rheumatoid arthritis and corresponding steps of macrophage intermediate or terminal (trans) differentiation

Cells of the MPS show clear signs of activation, not only in synovial and juxta-articular compartments such as the synovial membrane or the cartilage-pannus and bone-pannus junctions (including the subchondral bone), but also in extra-articular compartments (for example, peripheral blood and subendothelial space, the latter of which is the site of foam cell formation and development of atherosclerotic plaques in RA) (Table (Table2).2). This activation underlines the systemic inflammatory character of RA and may contribute to the occurrence of cardiovascular events and its increased mortality (reviewed in [2,14,15]).

Biological functions of monocytes/macrophages and their role in rheumatoid arthritis

The monocyte/M[var phi] system represents an integral part of the natural immune system and participates in the first-line response against infectious agents. Another crucial contribution to the body's homeostasis is the scavenging function of any debris generated by physiological or pathological processes. Thus, monocytes/M[var phi] possess multiple and powerful biological functions that may greatly affect onset and development of chronic inflammatory diseases like RA (see overview in Table Table3)3) (reviewed in [16]).

Table 3
Monocyte/macrophage functions and their (potential) role in rheumatoid arthritis

Stimulation/regulation of monocyte/macrophage activation in rheumatoid arthritis

The role of monocytes/M[var phi] in RA is conceivably the integrated result of stimulatory, effector, dually active, and autoregulatory mediators/mechanisms. At the tissue level, the scenario is characterized by the influx of pre-activated monocytes, their maturation into resident M[var phi], their full activation, and their interaction with other synovial cells. The complexity of the interaction is the result of paracrine activation mechanisms generated via sheer cell-cell contact as well as of numerous autocrine mechanisms – nearly any soluble mediator shows abnormalities. A simplified scheme of this integrated system and the currently known mediators is provided in Figure Figure2.2. For ease of presentation, the parts are organized as incoming stimuli (both paracrine and soluble) (column a) and effector molecules (column b), although autocrine loops are also relevant (as discussed below).

Figure 2
Paracrine, juxtacrine, and autocrine stimuli (column a) and effector molecules (column b) of macrophage (M[var phi]) activation in rheumatoid arthritis. Most of the regulatory products of activated macrophages act on macrophages themselves, creating autocrine ...

Cell-cell interaction

A significant part of M[var phi] effector responses is mediated by cell contact-dependent signalling with different inflammatory or mesenchymal cells (as exemplified in the lower left quadrant of Figure Figure22).

Fibroblast-macrophage interaction

Because of the prominent numbers of M[var phi] and fibroblasts and their activated status in RA synovial tissue, the interaction of these cells is critical for the resulting inflammation and tissue damage. Indeed, the mere contact of these cells elicits the production of interleukin (IL)-6, granulocyte macrophage colony-stimulating factor (GM-CSF), and IL-8. The cytokine output can be enhanced or down-modulated not only by addition of pro-inflammatory or regulatory cytokines (for example, IL-4, IL-10, IL-13, or IL-1 receptor antagonist [IL-1RA]), but also by neutralization of the CD14 molecule [17]. Also, in vitro, significant cartilage degradation occurs in co-cultures of mouse fibroblasts and M[var phi], a response markedly exceeding that observed with each culture alone (reviewed in [2]). Furthermore, purified human synovial fibroblasts co-cultured with myelomonocytic cells induce cartilage degradation in vitro, but with a strong contribution of soluble IL-1 and tumor necrosis factor (TNF)-α [18].

T cell-macrophage interaction

Accessory, inflammatory, effector, and inhibitory M[var phi] functions can be stimulated by fixed T cells or their plasma membranes if T cells are pre-activated and express activation surface molecules. In response to such interaction, monocytes produce metalloprotease (MMP), IL-1α, and IL-1β [19,20]. Also, T cells pre-stimulated in an antigen-mimicking fashion stimulate TNF-α and IL-10 production once in contact with monocytes [20]. Conversely, fixed T cells stimulated in an antigen-independent fashion (that is, with IL-15, IL-2, or a combination of IL-6 and TNF-α, the so-called Tck cells) induce monocyte production of TNF-α but not the anti-inflammatory IL-10 [20,21]. These findings suggest that early RA may reflect antigen-specific T cell-M[var phi] interactions [22]. Conversely, chronic RA may be associated with antigen-independent interactions dominated by an exuberant cytokine milieu and Tck cells. This may also explain the relative paucity of IL-10 in the synovial membrane in chronic RA, as discussed below.

Several ligand pairs on T cells and monocytes/M[var phi] have been implicated in this interaction [20], although the importance of individual ligand pairs, as well as the influence of soluble mediators, remains unclear. Interestingly, T cells isolated from RA synovial tissue show phenotypical and functional features similar to Tck cells and the above-mentioned signal transduction pathways differentially contribute to the induction of TNF-α and IL-10 production in monocytes/M[var phi] by co-culture with Tck cells. If applicable in vivo in RA, this would allow selective therapeutic targeting of pro-inflammatory TNF-α and sparing of anti-inflammatory IL-10.

Interaction of macrophages with endothelial cells and natural killer cells

The interaction between monocytes and endothelial cells in RA (Figure (Figure2),2), critical for the sustained influx of activated monocytes in the synovial membrane, relies on the altered expression of integrin/selectin pairs on the surface of the two cell types (reviewed in [2]). Because the synovial cytokine milieu (including the M[var phi]-derived TNF-α) upregulates the expression of these ligand pairs, a self-perpetuating cycle ensues by which sustained M[var phi]-derived mechanisms lead to further influx and activation of circulating monocytes. Upon cell contact, monokine-activated CD56bright natural killer cells induce monocytes to the production of TNF-α, thus representing another possible reciprocal loop of activation in RA [23].

Soluble stimuli

Cytokine stimuli with pro-inflammatory effects on macrophages

Numerous cytokines with known or potential stimulatory activity on monocytes/M[var phi] have been identified, as schematically shown in the upper left quadrant of Figure Figure2.2. A systematic list of these stimuli and their known or potential functions is provided in Table Table4.4. Some of these mediators are produced by monocytes/M[var phi] themselves and therefore activate M[var phi] in an autocrine fashion, as also exemplified in Table Table4.4. T-cell cytokines acting on M[var phi] (for example, IL-17) have been comprehensively reviewed elsewhere [24,25].

Table 4
Overview of pro-inflammatory interleukins relevant to macrophage (dys)function in rheumatoid arthritis

Bacterial/viral components and Toll-like receptors

The ability of bacterial toxins or superantigens to initiate the secretion of M[var phi]-derived cytokines is relevant in view of a possible microorganism etiology of RA and in view of side effects of anti-TNF-α therapy, particularly mycobacterial infections [26,27]. Lipopolysaccharide (LPS), for example, binds to M[var phi] through the CD14/LPS-binding protein receptor complex and, in vitro, stimulates the production of IL-1β, TNF-α, and macrophage inflammatory protein-1α. Staphylococcal enterotoxin B (SEB), a potent M[var phi] activator, enhances arthritis in MRL-lpr/lpr mice. Anti-TNF-α therapy, in this case, reverses both the severe wasting effects of SEB and the incidence of arthritis, indicating that TNF-α is central in this system. Finally, the staphylococcal enterotoxin A increases the expression of the Toll-like receptor (TLR)-4 in human monocytes by ligation of major histocompatibility complex-II, with subsequent enhancement of pro-inflammatory cytokines by known TLR-4 ligands (for example, LPS [28]).

TLRs are part of the recently discovered cellular pattern-recognition receptors (PPRs) involved in first-line defense of the innate immune system against microbial infections. In addition to bacterial or viral components, some PPRs recognize host-derived molecules, such as the glycoprotein gp96, nucleic acids, hyaluronic acid oligosaccharides, heparan sulfate, fibronectin fragments, and surfactant protein A (reviewed in [29]). In RA, notably, functional TLR-2 and TLR-4 are expressed on CD16+ synovial M[var phi], peripheral blood mononuclear cells, and synovial fibroblasts [30]. Also, their expression can be upregulated by cytokines present in the inflamed RA joint (for example, IL-1β, TNF-α, macrophage colony-stimulating factor, and IL-10); this suggests that activation of synovial cells via TLRs may contribute to disease processes [29], as supported by findings in experimental arthritis [31]. On the other hand, the chronic polyarthritis observed in mice with deletion of the DNase II gene, whose M[var phi] are incapable of degrading mammalian DNA, appears to occur independently of the nucleic acid-specific TLR-9 [32].

Hormones

Females are affected by RA at a ratio of approximately 3:1 compared with males and experience clinical fluctuations during the menstrual cycle and pregnancy, indicating a major modulating role for sex hormones. Due to their expression of sex-hormone receptors and their cytokine response upon exposure to estrogens, monocytes/M[var phi] are strongly involved in hormone modulation of RA [33]. Indeed, physiological levels of estrogens stimulate RA M[var phi] to the production of the pro-inflammatory cytokine IL-1, whereas higher levels inhibit IL-1 production, conceivably mimicking the clinical improvement during pregnancy. Interestingly, selective estrogen receptor ligands inhibiting nuclear factor (NF)-κB transcriptional activity (but lacking estrogenic activity) can markedly inhibit joint swelling and destruction in experimental arthritis [34].

Cytokine stimuli with regulatory effects on macrophages

In addition to pro-inflammatory cytokines, several cytokines that regulate monocyte/M[var phi] function in RA have been described (summarized in the upper left quadrant of Figure Figure2).2). A systematic list of these cytokines is provided in Table Table5.5. Interestingly, some of these molecules are produced by M[var phi] themselves (most notably, IL-10), so that autocrine regulation may also play a prominent role during the different clinical phases of RA. Other regulatory cytokines derive from other cell types present in the inflamed synovial membrane: T cells (for example, IL-4 and IL-13) or stromal cells (for example, IL-11). For these molecules, the reader is referred to recent publications or comprehensive reviews [25,35,36].

Table 5
Overview of anti-inflammatory cytokines relevant to macrophage (dys)function in rheumatoid arthritis

Monocyte/macrophage effector molecules in rheumatoid arthritis

Monocyte/macrophage effector molecules with proinflammatory effects in rheumatoid arthritis

M[var phi] produce a number of pro-inflammatory cytokines, as schematically shown in the upper right quadrant of Figure Figure2.2. A systematic list of the pro-inflammatory ILs is provided in Table Table44.

Tumor necrosis factor-alpha

TNF-α is a pleiotropic cytokine that increases the expression of cytokines, adhesion molecules, prostaglandin E2, collage-nase, and collagen by synovial cells. TNF-α exists in membrane-bound and soluble forms, both acting as pro-inflammatory mediators. Transmembrane TNF-α is involved in local, cell contact-mediated processes and appears to be the prime stimulator of the R75 receptor [37]. Interestingly, the transgenic expression of this form is alone sufficient to induce chronic arthritis [38]; likewise, a mutant membrane TNF-α, which uses both R55 and R75 receptors, can cause arthritis. Conversely, the soluble form of TNF-α, shed via MMP cleavage from the membrane-bound form, primarily stimulates the R55 receptor, acting transiently and at a distance [37].

In RA, TNF-α is mostly produced by M[var phi] in the synovial membrane and at the cartilage-pannus junction and possibly occupies a proximal position in the RA inflammatory cascade [39]. While an average of approximately 5% of synovial cells express TNF-α mRNA/protein in situ [40], the degree of TNF-α expression in the synovial tissue depends upon the prevailing histological configuration, resulting in different clinical variants [41]. Different disease stages and clinical variants are also reflected in serum and synovial fluid levels of TNF-α [42].

The critical importance of TNF-α in RA is supported by several experimental observations: (a) TNF-α in combination with IL-1 is a potent inducer of synovitis [43], (b) transgenic, deregulated expression of TNF-α causes the development of chronic arthritis [44], (c) TNF-α is produced in synovial membrane and extra-articular/lymphoid organs in experimental arthritides, mimicking the systemic character of RA [2], (d) neutralization of TNF-α suppresses experimental arthritides [39,43], and (e) administration of chimeric/humanized anti-TNF-α monoclonal antibodies or TNF-α receptor constructs has shown remarkable efficacy in acute disease and retardation of radiographic progression [3,7,11].

As an interesting development, the analysis of gene expression in monocytes of anti-TNF-α-treated patients with RA may represent a powerful tool to identify regulation patterns applicable for diagnosis and therapy stratification or monitoring [45,46] (Stuhlmuller B, Hernandez MM, Haeupl T, Kuban RJ, Gruetzkau A, Voss JW, Salfeld J, Kinne RW, Burmester GR, unpublished data). A reasonable expectation is that gene analyses also provide means to predict which patients are future responders to anti-TNF-α therapy.

Tumor necrosis factor-alpha receptors

TNF receptors are found in synovial tissue and fluid of patients with RA, especially in cases of severe disease [39]. There are two known TNF receptors, the R55 (TNF-R1) (high-affinity receptor) and the R75 (TNF-R2) (low-affinity receptor), which are expressed by both synovial M[var phi] and fibroblasts [47,48]. The two TNF receptors can operate independently of one another, cooperatively, or by 'passing' TNF-α to one another [37], a complexity that may explain the tremendous sensitivity of target cells (such as M[var phi]) to minute concentrations of TNF-α. TNF receptors can also be shed, binding to soluble TNF-α and hence acting as natural inhibitors in disease. Recent studies have demonstrated that TNF-R1 may be primarily responsible for pro-inflammatory effects of TNF-α, whereas TNF-R2 may predominantly mediate anti-inflammatory effects of TNF-α [48] (reviewed in [49]). Thus, selective blockade of TNF-R1, instead of broad blockade of all effects of TNF-α, may become an attractive therapeutic approach [48,50].

Interleukin-1

In the RA synovial membrane, IL-1 is found predominantly in CD14+M[var phi] [51]; also, IL-1 levels in the synovial fluid significantly correlate with joint inflammation [52]. The two existing forms of IL-1 (IL-1α and IL-1β) show some differences (for example, low protein homology, stronger pro-inflammatory regulation of the IL-1β promoter, and secretion of inactive pro-IL-1β versus expression of membrane-bound IL-1α activity) but also strong similarities (that is, three-dimensional structures of the essential domains, molecular masses of pro-peptides, and mature-form processing proteases), resulting in almost identical binding capacity to the IL-1 receptors and comparable function. In arthritis, IL-1 appears to mediate a large part of the articular damage, as it profoundly influences proteoglycan synthesis and degradation [43,53]. At the same time, IL-1 induces the production of MMP-1 and MMP-3 and enhances bone resorption; this is compatible with recent evidence from arthritis models and human RA suggesting that the tissue-destruction capacities of IL-1β may outweigh its genuine role in joint inflammation [53].

Interleukin-1 receptors

The IL-1 type I receptor (IL-1R1), which mediates cell activation via IL-1R accessory protein and IL-1 receptor-associated kinase (IRAK), is found on numerous cells in the synovial tissue of patients with RA [54]. In contrast, the type II receptor (IL-1R2) (also found in soluble form in serum), which lacks cell-activating properties and acts exclusively as a decoy receptor, is low in synovial tissue [55]. Similarly, IL-1RA, a soluble protein that blocks the action of IL-1 by binding to the type I receptor without receptor activation, has been detected only sporadically in RA synovial samples. In RA, the balance between IL-1 and its physiological inhibitor IL-1RA is therefore shifted in favor of IL-1, indicating a dysregulation crucial in promoting chronicity [53]. However, therapeutic application of IL-1RA (anakinra) appears to be only modestly effective in RA (reviewed in [56]). Therefore, it remains to be clarified whether the IL-1 pathway is a less suitable therapeutic target than TNF-α (for example, due to functional redundancy in the IL-1 receptor superfamily) or whether the biological molecule IL-1RA is suboptimal for therapy.

Interleukin-15

IL-15, a cytokine of the IL-2 family with chemoattractant properties for memory T cells, is produced by lining layer cells (including M[var phi]) and is increased in RA synovial fluid [57]. Notably, peripheral or synovial T cells stimulated with IL-15 induce M[var phi] to produce IL-1β, TNF-α, IL-8, and monocyte chemotactic protein-1 [21,57] but not the regulatory IL-10. Because IL-15 is also produced by M[var phi] themselves, this cytokine may (re)stimulate T cells, possibly self-perpetuating a pro-inflammatory loop [57]. The expression of IL-15 in the RA synovial membrane, its biological function, and its successful targeting in experimental arthritis have generated large expectations on the use of a fully humanized anti-IL-15 antibody in clinical trials [56-58].

Interleukin-18

In the RA synovial membrane, this cytokine of the IL-1 family is expressed in CD68+ M[var phi] contained in lymphoid aggregates. CD14+ M[var phi] of the RA synovial fluid also express the IL-18 receptor [59]. The pro-inflammatory role of IL-18 in arthritis (and its potential suitability as a therapeutic target in RA) is indicated by the following findings: (a) IL-18 treatment markedly aggravates experimental arthritis [59], (b) intra-articular overexpression of IL-18 induces experimental arthritis, (c) IL-18 is involved in the development of experimental streptococcal arthritis (a strongly M[var phi]-dependent model), (d) IL-18 is selectively overexpressed in the bone marrow of patients with juvenile idiopathic arthritis and M[var phi] activation syndrome [5], (e) IL-18 can stimulate osteoclast formation through upregulation of RANKL (receptor activator of NF-κB ligand) production by T cells in RA synovitis, and (f) IL-18 mediates its action via classic induction of TNF-α, GM-CSF, and interferon (IFN)-γ [59] or functional Toll-like receptors TLR-2 and TLR-4 in synovial cells [30] or else through the induction of synovial acute-phase serum amyloid proteins. The clinical relevance of synovial IL-18 is emphasised by its correlation with the systemic levels of C-reactive protein (CRP); also, IL-18 and CRP decrease in parallel in synovial tissue and serum following effective treatment with disease-modifying anti-rheumatic drugs [60]. In addition, peripheral blood mononuclear cells of RA patients show low levels of the IL-18 binding protein (a natural inhibitor of IL-18) and reduced sensitivity to stimulation with IL-12/IL-18, indicating profound dysregulation of the IL-18 system [61].

Interleukin-23

The genuine role of IL-23, a cytokine of the IL-12 family predominantly produced by M[var phi] or dendritic cells, is unclear due to the sharing of the p40 subunit with IL-12 [62]. IL-23 has prominent pro-inflammatory functions, since transgenic expression in mice leads to multi-organ inflammation and premature death. IL-23 promotes various T-cell responses potentially relevant to RA [62]. Recent studies in experimental arthritis have demonstrated that mice lacking only IL-12 (p35-/-) show exacerbated arthritis, whereas mice lacking only IL-23 (p19-/-) are completely protected from arthritis [63]. In addition, activation of M[var phi] derived from arthritis-susceptible rats is paradoxically associated with reduced levels of pro-inflammatory mediators but high expression of IL-23 (p19), whereas non-susceptible rats show the inverse phenotype. If these findings were transferable to human RA, IL-23 would have a pro-inflammatory role and IL-12 a protective one. At the present time, it is unclear whether these findings fit into the recently introduced M1/M2 paradigm of differential M[var phi] activation [64,65] and especially whether this paradigm can be exploited for a better understanding of the role of M[var phi] in RA.

Interleukin-27

IL-27, another cytokine of the IL-12 family, is expressed by monocytes/M[var phi] following common inflammatory stimuli and displays a variety of pro- and anti-inflammatory properties [66]. In support of a pro-inflammatory role in arthritis, neutralizing antibodies against IL-27p28 suppress experimental arthritis [67].

Chemokines and chemokine receptors

Chemokines (subdivided into the CXC, CC, C, and CX3C families) are small proteins specialized in differential recruitment of leukocyte populations via a number of transmembrane receptors. Chemokines not only favor monocyte influx into inflamed tissue, but also play a key role in activation, functional polarization, and homing of patrolling monocytes/M[var phi] [65]. Notably, monocytes/M[var phi] express only select types of the numerous chemokine receptors (for example, CCR1, 2, 5, 7, and 8 as well as CX3CR1), representing a partially specific basis for prominent trafficking of monocyte/M[var phi] in arthritis. In RA, synovial M[var phi] produce several chemokines (for example, CCL3 [or M[var phi] inflammatory protein 1α], CCL5 [or RANTES], and CX3CL1 [or fractalkine]) and at the same time carry chemokine receptors, indicating the presence of autocrine loops in disease (reviewed in [68]). At the same time, chemokines are upregulated by the M[var phi]-derived TNF-α and IL-1. Significantly, some chemokines expressed in synovial M[var phi] (for example, IL-8 and fractalkine) are powerful promoters of angiogenesis, thus providing a link between M[var phi] activation and the prominent neo-vascularization of the RA synovium [69]. In RA, angiogenesis may be further promoted via activation of M[var phi] by advanced glycation end products, whereas thrombospondin-2 seems to downregulate angiogenesis. Because the enlargement of the vascular bed potentiates the influx of activated monocytes, down-modulation of the chemokine system represents a multi-potential target of anti-rheumatic therapy, as indicated by the promising results of treatment with a CCR1 antagonist in RA [68].

Macrophage migration inhibitory factor

One of the first ILs ever discovered, migration inhibitory factor (MIF), is an early-response cytokine abundantly released by M[var phi]. MIF stimulates a number of M[var phi] functions in an autocrine fashion (for example, secretion of TNF-α, phagocytosis, and generation of reactive oxygen species [ROS]). In addition, MIF confers resistance to apoptosis in M[var phi] and synovial fibroblasts, thus prolonging the survival of activated, disease-relevant cells. In RA, MIF is overexpressed in serum and synovial tissue in correlation with disease activity. Also, polymorphisms in the promoter or coding region of the human MIF gene are associated with features of juvenile idiopathic arthritis or adult RA [70].

Monocyte/macrophage effector molecules with anti-inflammatory/regulatory effects in rheumatoid arthritis

M[var phi] also produce anti-inflammatory cytokines, most notably IL-RA and IL-10, both cytokines engaged in autocrine regulatory loops (shown in the lower right quadrant of Figure Figure2)2) (Table (Table55).

Interleukin-1 receptor antagonist

Differentiated M[var phi] constitutively express IL-1RA, which is upregulated by pro-inflammatory mediators, including IL-1 itself or GM-CSF, and induces strong anti-inflammatory effects. By means of this feedback mechanism, M[var phi] therefore contribute to the termination of inflammatory reactions (reviewed in [71,72]) (see above).

Interleukin-10

IL-10, a Th2- and M[var phi]-derived cytokine with clear autocrine functions, reduces HLA-DR expression and antigen presentation in monocytes and inhibits the production of pro-inflammatory cytokines, GM-CSF, and Fc-γ receptors by synovial M[var phi]. Consistently with cytokine and chemokine downregulation, IL-10 clearly suppresses experimental arthritis. In spite of IL-10 elevation in serum and synovial compartments of patients with RA [73], some studies suggest a relative deficiency of IL-10 [74]. A combined IL-4/IL-10 deficiency probably tilts the cytokine balance to a pro-inflammatory predominance. In addition, the ex vivo production of IL-10 by RA peripheral blood mononuclear cells is negatively correlated with radiographic joint damage and progression of joint damage, suggesting that high IL-10 production is protective in RA. Similarly to IL-4, however, treatment with recombinant IL-10 does not improve RA. This may be partially explained by upregulation of the pro-inflammatory Fc-γ receptors I and IIA on monocytes/M[var phi] (reviewed in [2]).

Monocyte/macrophage effector molecules with dual effects in rheumatoid arthritis

Cytokines with a dual role are indicated in Tables Tables44 and and55.

Interleukin-6

IL-6 is the most strikingly elevated cytokine in RA, especially in the synovial fluid during acute disease [75]. The acute rise is consistent with the role of IL-6 in acute-phase responses (Table (Table1).1). However, while IL-6 levels in the synovial fluid correlate with the degree of radiological joint damage, and IL-6 and soluble IL-6 receptors promote the generation of osteoclasts, this cytokine has phase-dependent effects; for example, it protects cartilage in acute disease but promotes excessive bone formation in chronic disease. While IL-6 is mostly produced by synovial fibroblasts and only partially by M[var phi], two findings suggest that the striking IL-6 rise is a prominent outcome of M[var phi] activation: (a) the morphological vicinity of IL-6-expressing fibroblasts with CD14+ M[var phi] in the RA synovial tissue (reviewed in [2]) and (b) co-culture studies showing that IL-1 stimulates IL-6 production [17]. The role of IL-6 in experimental arthritis and the anti-arthritic effects of anti-IL-6 receptor antibodies suggest a role for anti-IL-6 therapy in RA [76] (reviewed in [77]).

Transforming growth factor-beta

In RA, M[var phi] express different transforming growth factor-beta (TGF-β) molecules and TGF-β receptors in the lining and sublining layers, at the cartilage-pannus junction, and in the synovial fluid [78-80]. The pro-inflammatory effects of TGF-β are substantiated by induction of M[var phi] expression of Fc-γ receptor III (which elicits the release of tissue-damaging ROS) and promotion of monocyte adhesion and infiltration during chronic disease (reviewed in [80]). At the same time, TGF-β has anti-inflammatory properties; for example, it counteracts some IL-1 effects, including phagocytosis of collagen and possibly MMP production. A protective role of TGF-β in RA is also suggested by the association between TGF-β polymorphism and disease severity; that is, alleles associated with low TGF-β expression are correlated with stronger inflammation and poorer outcome [81]. Likewise, experimental arthritis is significantly ameliorated by activation of TGF-β via adenoviral expression of thrombospondin-1 [82]. The effects of TGF-β on tissue inhibitor of MMP (TIMP) are also unclear, as the regulation of MMP and TIMP may depend on different tissue domains (superficial versus deep cartilage layers) and may vary for intra- or extracellular digestion of collagen (reviewed in [2]).

Treatment of human rheumatoid arthritis with conventional anti-macrophage approaches

The role of M[var phi]-derived cytokines in the perpetuation of RA, the pathophysiological dichotomy between joint inflammation and cartilage destruction, and the crucial significance of activated synovial M[var phi] in relation to permanent joint damage [1] have led to a radical re-evaluation of the conventional anti-inflammatory and disease-modifying treatments in relation to M[var phi] parameters in order to potentiate therapeutic effects (for example, via combination approaches [83]) and reduce side effects. For anti-M[var phi] effects of conventional anti-rheumatic therapy in RA (including methotrexate, leflunomide, anti-malarials, gold compounds, corticosteroids, and non-steroidal anti-inflammatory drugs), the reader is referred to a recent comprehensive review [11]. Recent findings show that conventional and specific anti-rheumatic treatments predominantly target sublining rather than lining M[var phi]; also, different therapeutic approaches seem to result in similar histological changes in the inflamed synovial membrane, including significant reduction of sublining M[var phi]. This, in turn, is significantly correlated with the degree of clinical improvement [11,12]. Thus, different pathogenetic mechanisms may funnel into similar disease pathway(s), leading to massive activation of M[var phi] and providing the rationale for targeted anti-M[var phi] therapy.

Non-conventional and experimental anti-macrophage therapy

Counteraction of monocyte/macrophage activation at a cellular level

Apoptosis-inducing agents

Physical elimination of disease-relevant cells (for example, activated M[var phi] or osteoclasts) by apoptosis is advantageous because it circumvents secondary tissue damage by restraining cellular organelles in apoptotic vesicles. Phagocytic incorporation of liposome-encapsulated non-amino-bisphosphonates by activated monocytes, for example, induces apoptosis in these cells [84] (Figure (Figure3).3). Systemic application of encapsulated bisphosphonates in experimental arthritis not only counteracts joint swelling, but also prevents local joint destruction and subchondral bone damage [85]; in addition, it shows protective effects on remote bone damage. Studies in RA show that a single intra-articular administration of clodronate liposomes leads to M[var phi] depletion and decreased expression of adhesion molecules in the lining layer of RA synovial tissue [86]. Selective targeting of activated M[var phi] has also been demonstrated using either apoptosis-inducing immunotoxins coupled to anti-Fc-γ receptor I (CD64) antibodies or folate receptor-mediated targeting (reviewed in [2]). In general, liposome encapsulation can also be exploited for selective delivery of M[var phi]-modulating drugs [87] (reviewed in [2]) or gene therapy constructs (reviewed in [88]).

Figure 3
Potential and established approaches for modulation of monocyte/macrophage (M[var phi]) functions in rheumatoid arthritis. COX-2, cyclooxygenase-2; EC, endothelial cells; FB, fibroblasts; ICAM-1, intracellular adhesion molecule-1; IFN-β, interferon-beta; ...

Control of gene transcription

The transcription of most cytokine genes in monocytes/M[var phi] depends on the activation of NF-κB and NF-κM transcription factors or that of the activator protein-1 (AP-1) complex. In RA synovial M[var phi], the expression of NF-κB is more pronounced than that of AP-1, a selectivity that may bear important therapeutic implications [89]. Accordingly, the anti-arthritic effects of IL-4 may be based on the selective suppression of NF-κB in M[var phi]. IL-10 also downregulates the production of pro-inflammatory monokines, inhibiting the nuclear factors NF-κB, AP-1, or NF-IL-6. Unlike IL-4, IL-10 can also enhance degradation of the mRNA for IL-1 and TNF-α (reviewed in [2]). In general, therefore, targeted inhibition of 'pro-inflammatory' signal transduction pathways in M[var phi] represents an attractive therapeutic approach [90].

Gene therapy in experimental arthritis

Gene therapy has been applied in experimental arthritis models to counteract M[var phi]-derived IL-1 and TNF-α or to deliver/overexpress protective IL-1RA, soluble IL-1 type I receptor-IgG fusion protein, and type I soluble TNF-α receptor-IgG fusion protein. This has been extended to (M[var phi]-derived) anti-inflammatory cytokines (that is, IL-4, IL-10, IL-13, IFN-β, or TGF-β) and to 'molecular synovectomy' (either by expression of herpes simplex virus-thymidine kinase with subsequent administration of ganciclovir or by overexpression of Fas-ligand/inhibitors of nuclear translocation of NF-κB, resulting in synovial cell apoptosis [88,91,92]). Therefore, gene therapy aimed at neutralizing pro-inflammatory M[var phi] products, overexpressing M[var phi]-regulating mediators, or simply eliminating overly activated M[var phi] remains promising for the treatment of arthritis.

Conclusion

The multitude and abundance of M[var phi]-derived mediators in RA and their paracrine and autocrine effects (including those directed to other cells of the myeloid lineage) indicate that M[var phi] are local and systemic amplifiers of disease severity and perpetuation. The main local mechanisms include (a) self-perpetuating chemokine-mediated recruitment of inflammatory cells, (b) cytokine-mediated activation of newly immigrated inflammatory cells, (c) cell contact-mediated activation of neighboring inflammatory cells, (d) cytokine- and cell contact-mediated secretion of matrix-degrading enzymes, (e) activation of mature dendritic cells and cytokine-mediated differentiation of M[var phi] (and possibly B cells, T cells, and mesenchymal cells) into antigen-presenting cells, with possible effects on spreading of autoimmunity to cryptic epitopes, (f) neo-vascularization, with potentiation of cellular and exudatory mechanisms, and (g) (trans)differentiation of M[var phi] into osteoclasts involved in subchondral bone damage. At a systemic level, amplification of disease can proceed at least through the following mechanisms: (a) acute-phase response network, (b) systemic production of TNF-α, (c) anomalies in bone marrow differentiation, and (d) chronic activation of circulating monocytes.

Although uncovering the etiology of disease remains the ultimate goal of research, the efforts in understanding how activated M[var phi] influence disease have led to optimization strategies to selectively target activated M[var phi] in RA (Figure (Figure3).3). This approach has at least two advantages: (a) striking the very cell population that mediates/amplifies most of the irreversible cartilage destruction and (b) minimizing adverse effects on other cells that may have no (or marginal) effects on joint damage.

Abbreviations

AP-1 = activator protein-1; CRP = C-reactive protein; GM-CSF = granulocyte macrophage colony-stimulating factor; IFN = interferon; IL = interleukin; IL-1RA = interleukin-1 receptor antagonist; LPS = lipopolysaccharide; M[var phi] = macrophage(s); MIF = migration inhibitory factor; MMP = metal-loprotease; MPS = mononuclear phagocyte system; NF = nuclear factor; PPR = pattern-recognition receptor; RA = rheumatoid arthritis; ROS = reactive oxygen species; SEB = staphylococcal enterotoxin B; TGF-β = transforming growth factor-beta; TIMP = tissue inhibitor of metalloprotease; TLR = Toll-like receptor; TNF = tumor necrosis factor; TNF-R1 = tumor necrosis factor receptor 1; TNF-R2 = tumor necrosis factor receptor 2.

Competing interests

The authors declare that they have no competing interests.

Note

This review is part of a series on Cells of the synovium in rheumatoid arthritis edited by Gary Firestein.

Other articles in this series can be found at http://arthritis-research.com/articles/review-series.asp?series=ar_Cells

Acknowledgements

Ernesta Palombo-Kinne is gratefully acknowledged for critical revision of the manuscript. This study was supported by the German Federal Ministry of Education and Research (BMBF) (grants FKZ 01ZZ9602, 01ZZ0105, and 010405 to RWK), the Interdisciplinary Center for Clinical Research (IZKF) Jena, including grants for junior researchers, (grants FKZ 0312704B and 0313652B to RWK), the Jena Centre for Bioinformatics; (grant 01GS0413, NGFN-2 to RWK); the German Research Foundation (DFG) (grants KI 439/7-1/3 and KI 439/6-1/3 to RWK); the Thuringian Ministry of Science, Research, and Art (FKZ B 311-00026); and a grant for the advancement of female scientists (LUBOM Thuringia).

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