Clin Exp Nephrol (2010) 14:1–11 DOI 10.1007/s10157-009-0218-y

REVIEW ARTICLE

Dendritic cells and macrophages in kidney disease Koichi Matsumoto Æ Noboru Fukuda Æ Masanori Abe Æ Takayuki Fujita

Received: 10 September 2008 / Accepted: 9 July 2009 / Published online: 18 August 2009 Ó Japanese Society of Nephrology 2009

Abstract Recent studies on dendritic cells (DCs) and macrophages have greatly advanced our knowledge of glomerular immunopathology. This rapidly developing field most likely has considerable impact on our understanding of the major mediators of tissue injury and repair in kidney disease. The pivotal role of cytokine in the initiation, differentiation, and amplification of local immune response production by antigen-presenting cells (APC; DCs, macrophages, and so forth) has been well documented, but the precise biological role of the numerous APC-derived products as effectors in both renal inflammation and repair remains a topic of intense research. This review focuses on the activated DCs and macrophages for the development and resolution of kidney disease, and discusses mechanistic information on the inflammatory process, including tissue injury and healing. A multidimensional study may contribute to further clarification of the role of their cellular activation in the progression of human kidney disease. Keywords Dendritic cells
Macrophages
Toll-like receptors
Kidney
Glomerulonephritis
IgA nephropathy
Focal glomerular sclerosis

This article was presented at the 51st Annual Meeting of the Japanese Society of Nephrology. K. Matsumoto (&)
N. Fukuda
M. Abe
T. Fujita Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kami-Machi, Itabashi-ku, Tokyo 173-8610, Japan e-mail: [email protected]

Introduction Antigen-presenting cells (APCs) play an important role in the early stage of the immune response by linking innate immune responsiveness with the generation of the adaptive immunity. In recent years, much study has focused on the responses of innate cells to stimulation through the Tolllike receptors (TLRs). A total of 13 mammalian TLRs paralogues (11 are expressed in humans) have now been described. In addition to its role in primary innate responses, differential TLR ligation is now also known to drive the development of subsequent adaptive immunity. The outcome of an immune response depends highly on the type and activation state of the APCs and their ability to produce certain cytokines and chemokines. Dendritic cells (DCs) are the most potent APCs, and they can activate naı¨ve T cells in vitro and also play the most important role in the initiation of the primary immune response in vivo. DC subpopulations and macrophages communicate both by means of direct cell–cell interactions and through the production of inflammatory signals. Macrophages represent a diverse population of cells with specialized roles in health and disease. When activated, they express a wide array of factors that influence immune reaction and define the nature of tissue remodeling. Recent studies have focused on the role of APCs, particularly on the role of DCs and macrophages in the onset and the progression of renal pathology. Certainly, animal experiments should help to provide more direct evidence about the roles of their cells, especially in terms of progression or resolution of kidney disease. Because of their dynamic nature and ability to exchange molecular information with neighboring cells, DCs and macrophages represent a potentially attractive target for strategies aimed at progressive kidney disease. Further elucidation of their

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cells will open an avenue for understanding the pathophysiology involved in the induction of renal injury.

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responses. In addition, pDCs may play a pivotal role in inducing regulatory T cells and gaining an immunological tolerance.

Dendritic cells Dendritic cells in experimental glomerulonephritis Dendritic cells are commonly found as precursor populations from myeloid and lymphoid lineages in bone marrow and blood, and as more mature forms in tissues of nonlymphoid origin as well as in the T cell zones of lymphoid organs [1]. It has long been known that naı¨ve T cells require stimulation before they can promote immune responses [2]. The crucial process is accomplished by DCs in secondary lymphoid organs. In addition to the classical DC function, non-migratory DCs that reside in non-lymphoid organs can affect the response of infiltrating CD4? T cells [1, 3]. In the kidneys of rodents, the phenotypic features of DCs have been reported by flow-cytometrical and electron microscopic studies [4, 5]. The DC network serves to mediate the glomerular immunopathology [5]. Inflammation is a characteristic of both acute and chronic progressive renal diseases. The pathophysiology of renal inflammation is complicated and multifaceted, involving the interaction of cytokines, chemokines, and adhesion molecules. It is reported that DCs play an immunomodulatory role in the continuity of tolerance as well as mounting sturdy immune responses to pathogens [6]. They are extremely effective APCs and provide antigens to T cells in the context of various costimulatory molecules. Though it is well known that DCs produce cytokines and chemokines, very limited information is available about how their synthesis is controlled during DC growth. Functionally distinct DC subsets, releasing cytokines such as interleukin (IL)-12, IL-10 and IL-4, induce T cell differentiation when stimulated via their TLRs [7]. Accordingly, naı¨ve T cells must be activated before they can drive any immune response. This activation process is carried out by professional APCs, the DCs. Thus, DCs may determine the induction of T helper (Th)1, Th2 or Th3/ Treg responses. In addition, TLRs-activated DCs induce naı¨ve T cells to mature into antigen-specific effecter T cells, particularly of the Th1 lineage [1–3]. Thus, the analysis of TLRs expression and associated signaling pathways may reveal the molecular basis of the differential response of DCs to pathogenic antigens. Dendritic cells and macrophages play crucial roles in the development or resolution of renal inflammation (Fig. 1). Both cells are able to induce dynamic alterations in their function and phenotypes [8–11]. In general, DCs are classified into myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) [12]. Human mDCs express both BDCA-1 and DCSIGN, while pDCs are positive for BDCA-2. Moreover, DCs can be controlled to either stimulate or suppress T cell

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Although renal DCs have been examined less actively than macrophages, several studies have shown the implication of the DCs in the pathophysiology of glomerulonephritis (GN) [13–15]. The exact biological relevance and underlying mechanisms of DCs response remain to be clarified [16–18]. In a rodent model of human anti-glomerular basement membrane (GBM) disease, large numbers of CD11c? cells identified as DCs were detected in the tubulointerstitium [13]. Local accumulation of mononuclear infiltrates was seen within the tubulointerstitium and adjacent to, but not within the inflamed glomeruli [13]. These cells were remarkably infiltrated into injured sites, suggesting that diverse molecules such as inflammatory cytokines and chemokines are crucial in the DC influx. The functional role of renal DCs in experimental nephrotoxic serum nephritis (NTN) remains unclear. They may be engaged in the amelioration of immunopathology, but they may also play a primary pathogenic role in the development of GN. In investigations trying to answer these questions, in vivo studies to preferentially remove DCs have been performed [15]. To examine the in vivo role of renal DCs in NTN, CD11c? DCs were depleted on days 4 and 10 after the initiation of NTN [15]. The removal of DCs caused reverse effects such as deteriorated tubulointerstitial and glomerular injury, decreased creatinine clearance, and increased proteinuria. Thus, renal DCs were likely to attenuate the NTN injury, which might act to reduce the inflammatory processes by the production of IL10 and so forth. IL-10 production by DCs in the inflamed kidney is crucial in mediating tolerance to pathogenic antigens. IL-10 can inhibit IL-12 production, can downregulate antigen presentation, and is required for the action of some regulatory DCs. DCs appear to represent a counterregulator and ameliorate kidney disease, probably by inducing IL-10 production [15]. In view of the data defined in the NTN model, one could postulate a protective role of local DC influx in affecting the pathophysiology in NTN. It is thus possible that DCs infiltrate into the inflamed tubulointerstitial space and have actual relevance to the resolution of local inflammatory responses. This would prove DCs to be anti-inflammatory mediators participating in an action to reduce pathogenic responses in experimental NTN. Conflicting results exist concerning the relevance of macrophages in experimental GN. Using a similar NTN model, earlier studies have suggested that the grade of

Clin Exp Nephrol (2010) 14:1–11 Fig. 1 A simplified schema of potential pathogenic mechanisms of cell involvement in inflammatory injury. Renal dendritic cells and macrophages may play a part in promoting the development of Th1 and Th17 cells, which drive cellular immune responses and may induce renal inflammation, or even their regulation. TNF-a Tumor necrosis factor-a, G-CSF granulocyte colony stimulating factor, PGE2 prostaglandin E2

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IL-12R IL-12

Th1

Macrophage/monocyte IL-23R IL-23

Dentritic cell

injury correlates with the intensity of the glomerular and interstitial macrophage infiltrate [19]. Taken together, the two renal intrinsic APCs, DCs and macrophages, are likely to work conversely in NTN, possibly by differentially affecting the phenotypes of infiltrating CD4? T cells [17]. A series of preliminary studies in experimental models show that the handling of such cells may suppress the development of renal injury and may contribute to a novel therapeutic approach in human kidney disease.

Dendritic cells in the human kidney Dendritic cells play a key role in immune responses and can be classified into two major subsets, i.e., mDCs and pDCs [12]. Renal DCs were first described in rats as Ia? (major histocompatibility complex class II?) cells present in the interstitium in immunohistochemical studies by Hart and Fabre in 1981 [20]. Very limited information is available about the role of DCs as part of the infiltrate in the human kidney. A quantitative evaluation of DC subsets in the human kidney was recently performed by Woltman et al. [21]. They have shown a complicated network of interactions within the kidney by which both mDCs and pDCs participate in inflammatory renal injury. Dendritic cells and macrophages are heterogeneous and highly dynamic bone marrow-derived cells that play critical roles in kidney disease. Segerer et al. [22] identified these cells using immunohistochemistry in renal biopsy specimens from patients with GN. In proliferative GN, numerous CD68 positive (pan monocyte, macrophage and DCs marker) cells were found in both glomerular and tubulointerstitial areas, but on the other a mDCs marker (DS-SIGN) was detected only in the tubulointerstitium. A large number of pDCs (recognized as BDCA-2 positive cells) were seen at sites of interstitial inflammation. Thus, the CD68 positive cells infiltrating in the glomerulus were deficient in DCs markers (reflecting macrophages), while in the tubulointerstitial area the majority of CD68-positive cells are also DC-SIGN positive (identified as mDCs). Their number

Th17

IL-1 IL-6 IL-8 α TNF-α G-CSF PGE2

IFN- γ

IL-17

Epithelial cells Endothelial cells Mesangial cells Fibroblasts

Inflammatory response

correlated well with the level of serum creatinine, further suggesting that the activation of renal DCs appears to play a functional role in progressive kidney disease. IgA nephropathy (IgAN) is the most common form of primary GN. A dysregulation of the mucosal immune response of IgAN patients might play a key role in the pathophysiology [23]. It was demonstrated that DCs from IgAN patients had an impaired capacity to stimulate IgA production in naı¨ve B cells, which might suggest the observed IgA hyporesponse upon mucosal injury with a neoantigen [23]. Renal function and its clinical prognosis correlate well with tubulointerstitial injury rather than with that of the glomeruli. Thus, the large numbers of infiltrating DCs can exert a primary influence on the development of kidney diseases once they infiltrate to the tubulointerstitial area. The infiltrating DCs can synthesize immunoregulatory cytokines upon contact with a pathogen. In support of this notion, DCs have been found to induce periglomerular infiltrates around the inflamed glomeruli in IgAN [22]. It is therefore suggested that the activated pDCs accumulate in large numbers in the kidney of the IgAN patients and regulate local immune responses against incessant auto and foreign antigens.

Involvement of Toll-like receptors in kidney disease TLRs are pattern recognition receptors that recognize pathogen-associated molecular patterns and signal through adaptor molecules, myeloid differentiation factor 88 (MyD88), Toll/IL-1 receptor domain containing adopter protein (TIRAP), Toll/IL-1 receptor domain containing adopter including interferon (INF)-b (TRIF), and TRIFrelated adapter molecule (TRAM) to active transcription factors, nuclear factor-jB (NF-jB), activator protein 1 (Ap-1), and INF regulatory factors (IRFs) leading to the trigger of innate immunity [24–26]. In the kidney, mesangial cells and tubular epithelial cells express TLR1 through 4 and 6 [26]. Previous in vitro

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studies have suggested that TLR-activated DCs induce naı¨ve T cells to mature into antigen-specific effecter T cells, particularly of the Th1 lineage [26]. This system promptly initiates host defenses against invading microbes [24–26]. TLRs are now known to participate in a number of other innate immune processes such as phagocytosis and the production of metalloproteinases. TLRs are also known to be crucial in a wide range of other more fundamental cellular processes, such as actin polymerization, angiogenesis, and the induction of apoptosis [24–26]. Recognition of distinct microbial features and discrimination of potential harmful pathogens from ‘self’ are essential parts of the innate immune system. The innate immune responses are orchestrated by some sort of patternrecognition receptors, most especially the TLRs in humans. Infection may exacerbate an autoimmune disease such as GN. TLRs belong to a family of receptors that recognize endotoxin and other ligands derived from pathogens. They are likely to play a pivotal role in the aggravation of kidney disease by infection. The precise mechanisms by which intrinsic renal cells and DCs participate in disease progression are not clear, but there is evidence supporting the theories related to triggering by exogenous or even endogenous signals via TLR ligation [24–26]. A number of more logical approaches have been explored to study the role of TLRs in kidney diseases [24– 26]. We then discuss the involvement of TLRs in the context of kidney disease. Patole et al. [27] have demonstrated the distribution of TRL on mesangial cells by mRNA expression profiles and flow cytometry. It is also established that human and murine mesangial cells express TLR1–TLR4, of which TLR3 is localized in intracellular endosomes [27]. This is in accordance with the accumulation of TLR3 in human renal biopsies [28]. In addition, TLR3 expression in renal biopsies was detected in vascular smooth muscle cells and cells of collecting tubules [28]. TLR4, in conjunction with CD14, is well characterized as the receptor for lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria. In the current study, TLR4, a family of pattern recognition receptors that respond to endotoxin, mediated increases in IL-1b, tumor necrosis factor (TNF)-a, and IL-6 in spleen cells [29]. Added to this, TLR4 expression is positive in tubular cells of all nephron segments [29]. From an experimental viewpoint in cultured mesangial cells and tubular epithelial cells, it has been proven that intrinsic renal cells express TLR1–TLR4, but the expression of TLR7–TLR9 is missing [27–30]. Stimulation with TNF-a and IFN-c induces TLR2–TLR4 and TLR6 in mesangial cells, whereas all TLR mRNA is downregulated by these cytokines in macrophages [27]. These findings suggest the participation of renal cells as a local sensor against microbial infection.

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Different TLR triggers evolve into anti-GBM-induced nephritis, as proven by the increased proteinuria and blood urea nitrogen. TLR2 on both leukocytes and resident renal cells is able to promote the amplification of neutrophil influx [31]. TLR2 has been demonstrated to act as a receptor for components of gram-positive bacteria such as peptidoglycan and lipoteichoic acid. Activation of the receptors by their ligands can lead to production of proinflammatory cytokines such as TNF-a and IL-6, which are characteristic of glomerular inflammation. As expected, the renal inflammation induced by passive administration of nephrotoxic antibody does not occur in the absence of TLR2 stimulation, showing an intense synergy when antibody deposition and TLR2 stimulation occur together [31]. Indeed, Fu et al. [32] have demonstrated that in an NTN model, the activation of TLR2, TLR3, TLR4, and TLR5 by using peptidoglycan, LPS, and flagellin could promote the antibody-mediated inflammation and tissue injury with a production of proinflammatory cytokines and chemokines, including IL-1, IL-6, TNF-a, and monocyte chemoattractant protein (MCP)-1. TLR2 on both leukocytes and resident renal cells is able to induce the reinforcement of neutrophil influx. Their data have also shown that TLR2deficient mice had a decreased glomerular neutrophil infiltration, in spite of possessing a larger number of peripheral neutrophils [32]. Hence, the TLR2 deficit appears to play a key role in the resolution of the experimental GN [32]. A major advance in the area demonstrated participation in the matrix molecule biglycan as a ligand for TLR4 and TLR2 [33]. They have shown that biglycan acts in macrophages as an endogenous ligand of TLR4 and TLR2, which mediate innate immunity, leading to rapid activation of NF-jB. Their results provide evidence for a novel role of the matrix component biglycan as a signaling molecule and a crucial proinflammatory factor [33]. A study in a mesangial and tubular cell line disclosed the expression of TLR2 and TLR4 [27, 30]. The tubular cells are an immunologically active component, known to synthesize a number of cytokines and chemokines [34]. Heat shock proteins (HSP) are produced by renal cells in response to stress signals and local infection. It is hypothesized that pathogenic bacteria stimulate the cells in the kidney to up-regulate the expression of HSP60, which would stimulate DCs and macrophages, and possibly other parenchymal cells, to produce proinflammatory cytokines. HSP60 was recently recognized as an endogenous mediator that can be synthesized by tubular epithelial cells upon local injury [35]. Indeed the administration of HSP60 accelerates the progression of NTN in a TLR-dependent manner [35]. It is reasonable to postulate that mediators such as HSP60 may participate in the TLR2-mediated immune activation during tubular damage [36].

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A recent investigation has demonstrated a potential role of TLR7 in the activation of renal macrophages participating in the regional production of proinflammatory mediators such as IL-12, IL-6, and IFN-c, some of which were demonstrated to be potentially pivotal for the progression of lupus nephritis [37]. In fact, another investigations support a role for TLR7 in the generation of autoantibodies and in the development of murine lupus nephritis [24, 38]. Human neutrophils possess all TLRs except for TLR3. TLR9 is not expressed by tubular cells [27–30], and therefore the contribution of TLR9 to renal DNA viral infection remains unclear. However, Pawar et al. [39] have recently provided interesting data showing that TLR9 participates in the synthesis of specific autoantibodies, and the stimulation of the innate immune system with a specific nucleic acid agonist for TLR9 deteriorates the immunopathology of lupus nephritis in mice. Of the 13 known TLRs, recent studies have suggested that TLR9 may play the primary role in systemic autoimmunity [39]. Accordingly, it is possible that TLR9 signaling is also involved in immune responses in the murine kidney and even plays a role in the pathogenesis of lupus nephritis [39].

Macrophages as effectors in renal injury Macrophages are essential inflammatory cells and crucially implicated in renal injury. Some studies have demonstrated the presence of activated macrophage in the diseased kidney [40–42]. Production of pro-inflammatory cytokines by cultured glomeruli isolated from diseased human and animal kidneys was thought to be due to the presence of a large number of activated macrophages [40–42]. Subsequent immunohistochemical staining of renal biopsies has demonstrated that infiltrating macrophages actually synthesize pro-inflammatory cytokines, but other glomerular cells, notably podocytes and mesangial cells, also can produce these pro-inflammatory cytokines [43, 44]. Thus, it should be kept in mind that many mediators that were first demonstrated as macrophage products can be produced by a range of different cell types. Macrophage migration inhibitory factor (MIF) is a potent immunomodulator derived from activated monocytes/ macrophages, DCs, and T lymphocytes [45–47]. MIF has also been demonstrated to be a crucial cofactor in T cell activation [46]. MIF may function as an autocrine growth factor in certain cell systems [45–48]. MIF induces both systemic and local acute-phase responses, including the secretion of proinflammatory cytokines and growth factors [47]. Recent evidence suggests that mesangial cells can produce MIF in vivo and in vitro [49]. The pathological importance of excess MIF is evident in rat experimental

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GN; the number of MIF-secreting cells is locally increased in the diseased glomeruli of rat anti-thymocyte 1 nephritis [49]. In the kidney, MIF is produced not only by mesangial cells and infiltrating macrophages, but also by glomerular epithelial cells and glomerular endothelial cells [50], and by tubular cells [50, 51]. The comparative overproduction of MIF in rat crescentic GN [50] further substantiates the postulation that MIF is a key upstream regulator of glomerular inflammation. These findings indicate an important role of MIF-mediated immune responses in inflammatory conditions of the glomeruli. In the current studies, a number of proinflammatory cytokines and transcription factors have been demonstrated as pivotal components in the pathogenesis of experimental kidney disease. The macrophage accumulation is associated with an increase of the proinflammatory cytokines and chemokines, two mediators important in the recruitment and activation of macrophages. Angiotensin II is capable of inducing MCP-1 production through the activation of transcription factor NF-jB [52]. NF-jB is a pivotal transcription factor for genes that encode the proinflammatory cytokines, chemokines, and adhesion molecules that mediate inflammation. The prevention of the renin/angiotensin activity resulted in the suppression of NF-jB activity and MCP-1 expression by both glomerular and tubular cells, together with the reduction of interstitial macrophage influx and proteinuria [53, 54]. These findings suggest the crucial involvement of the rennin/angiotensin system in the development of interstitial injury through mechanisms other than regulation of hypertension. Suppression of the system comes into use in clinical nephrology. The valid effects of angiotensin II blockade are likely to be mediated by the inhibitory effects on macrophage infiltration and activation.

Modification of macrophage function in kidney disease Conflicting reports exist concerning the involvement of macrophages in GN. Macrophage infiltration is one of the most evident characteristics of both glomerular and tubulointerstitial damage, and the extent of the mononuclear cell infiltrate has been examined to predict subsequent prognosis [44, 55]. The definition of macrophage activation states comes from works by Gordon [10] and Mosser [11], which show the activation state characteristics: classically activated macrophages, alternatively activated macrophages, type II activated macrophages, and macrophages activated by uptake of apoptotic cells. Indeed, macrophages can be manipulated in a classic (IFN-c-dependent) and alternative manner (by Th2 cytokines), changing into proinflammatory versus anti-inflammatory phenotypes [10, 11]. These alterations in phenotypes likely reflect the adjustment to diverse local environments. Thereby, their

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phenotypes might not only be engaged in the development of the renal injury, but could also induce tolerance or repair responses. Several authors have reported that macrophages are key promoters in renal inflammation and multifunctional cells that may provoke tissue injury or facilitate repair [56–58]. Inflammatory macrophages are active participants that may induce apoptosis in both mesangial and tubular epithelial cells in vitro [59] and regulate tissue remodeling. The elimination of macrophages and lymphocytes from the inflamed kidney has been examined. The removal of macrophages diminished the glomerular crescent formation and tubular cell apoptosis [60]. Interestingly, it has recently shown that the defective clearance of apoptotic cells may induce an activation of infiltrating macrophages and promote ongoing renal inflammation [61]. Macrophage apoptosis has also been demonstrated in rat anti-GBM GN [62]. Macrophage apoptosis and macrophage proliferation were mainly restricted to the areas of focal injury, such as glomerular crescents. Thus, apoptosis may be an important mechanism in the progression or resolution of macrophagemediated renal injury, suggesting a turnover of macrophages within the kidney. Recent work, however, has demonstrated that macrophage depletion using liposomal clodronate in rodent model of renal injury decreased the grade of tubular necrosois and apoptosis and lowered proinflammatory cytokine expression at the messenger ribonucleic acid level [63]. The precise mechanisms of macrophages in the abrogation of glomerular inflammation and associated glomerular remodeling are still not clear. The implication of modified macrophages can reform glomerular injury, and this may be brought about, at least in part, by reprogramming to an anti-inflammatory phenotype [64–66]. Macrophages, alternatively, may have an effect on the abrogation of inflammatory responses by the production of IL-10, transforming growth factor (TGF)-b, and so forth [10, 11]. The systemic utilization of modified macrophages can reduce injury, and this may be associated, at least in part, with the reprogramming of bystander macrophages. Several studies have shown that the administration of overabundant IL-10, IL-4, or IL-1 receptor antagonist or an antagonist of the NF-jB could attenuate glomerular and interstitial inflammation in various experimental models [67–71]. An actual characteristic of this strategy is that the nature modification of macrophages may be able to potentially change the phenotype of activated infiltrating macrophages and intrinsic renal cells [64–66]. However, the systemic administration of agonists/antagonists actually affects not only activated macrophages, but also all cells involved in renal inflammation. Thus, the complex relation between resident renal cells and infiltrating macrophages shows how modified

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macrophage function can prevent a local inflammatory response. Further to phenotypic changes, these tactics provide a theoretical logic to changing macrophage activation to control renal injury. The facts emphasize the potential of macrophages as a therapeutic target in immune-mediated renal disease. It highlights the importance of the activated macrophages for the development and resolution of renal disease. Clearly the modification of macrophage function provides a clue to prevent harmful inflammatory responses. TGF-b is a pleiotropic cytokine with diverse roles in inflammation and tissue fibrosis [72]. Macrophages also are a major source of TGF-b1, which plays a pivotal role in the progression of glomerulosclerosis [73, 74]. These findings suggest that the blockade of TGF-b1 by multiple strategies suppresses renal fibrotic lesions and prevents the progressive loss of renal function. But more importantly, it has become quite clear that TGF-b inhibits the synthesis of various cytokines by activated T cells and natural killer cells [72]. Accordingly, a recent report also showed that transgenic mice with overexpression of TGF-b1 are actually protected against the development of renal fibrosis, primarily through its anti-inflammatory function [75]. Therefore, an essential function of TGF-b1 is considered to be its anti-inflammatory effect. In spite of the crucial evidence that TGF-b1 participates in the progression of glomerular fibrosis [73, 74], the transgenic mice that overexpress human latent TGF-b1 in the skin disclosed normal renal histopathology and function, even though the circulating levels of latent TGF-b1 are an order of magnitude higher than in wild-type animals [76]. New evidence is emerging that mice overexpressing latent TGF-b1 in the skin are protected against anti-GBM crescentic GN, possibly via Smad7-mediated inhibition of NF-jB-dependent renal inflammation and TGF-b1/Smad2/3-dependent fibrosis [76]. These findings suggest a profitable effect of TGF-b1 in down-regulating macrophage-mediated glomerular injury. Macrophages are also involved in the resolution of inflammation. Recently, it has been shown that activated renal macrophages are markers of disease onset and disease remission in experimental lupus nephritis [77]. Schiffer et al. [77] have suggested that the activated renal macrophages were phenotypically different both from peripheral blood monocytes and from the resident macrophages found in young NZB/W kidneys. Although the model may not precisely mimic human disease, the model permits testing the effects of potential novel strategies. Given the diverse range of functions macrophages can assume, it becomes possible to modulate kidney disease by changing both macrophage activity and programming rather than simply trying to inhibit macrophage infiltration into inflamed glomeruli [64–66].

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Infiltrating macrophages are key to the induction of immune responses, depending on how they are activated by the regional circumstances. Macrophages regulate a wide range of diverse functions that are critical in tissue destruction and protection. Both infiltrating leukocytes, particularly macrophages and T cells, and parenchymal renal cells are potentially involved in directing and influencing renal inflammation. The heterogeneity of activated macrophages is characterized by different functional activation states [10, 11]. The phenotypic properties of macrophages rather than their absolute number reflect genetic susceptibilities to experimental GN [66–71]. An attractive approach to delivering genes into glomeruli to manipulate macrophage function is to change macrophage phenotype using transfection techniques and then send these genetically modified cells to inflamed glomeruli [69, 70]. Macrophages are sensitive to transfection with recombinant adenoviruses, and the macrophages manipulated in this way have been demonstrated to migrate selectively to the inflamed glomeruli in rats with NTN [69] and in mice treated with LPS [78]. Kluth et al. [70] have recently applied a system of IL-4-transfected macrophages with adenoviral vector. The adenoviral transfection with IL-4 resulted in a dramatic reduction in proteinuria, inflammatory cell influx, and glomerular injury [70]. The administration of macrophages overexpressing IL-1 receptor antagonist was able to reduce proteinuria in mice with inflammatory GN [78]. In view of the impressive effect, further investigation needs to be done looking at an exact effect of genetic manipulation of macrophages in vivo. Prospective therapeutic strategies aiming at alteration of the immune response through the manipulation of macrophage interactions by the use of transfection techniques capable of modifying cell function will be explored.

Macrophages in crescentic glomerulonephritis Macrophages are capable of producing a wide range of potentially cytotoxic products, including proinflammatory cytokines, chemokines, proteolytic enzymes, reactive oxygen and nitrogen species, and eicosanoids. The relative contribution of leukocytes and intrinsic renal cells in the production of these mediators is becoming increasingly apparent with studies in human and experimental GN [79, 80]. Our initial studies focused on the pathogenic properties of macrophages by using glomerular culture approaches [40–42]. To investigate the role of cytotoxic products in the pathophysiology of human rapidly progressive crescentic GN (RPGN), we examined IL-1 activity in the culture supernatant of glomerular cells from patients with RPGN [40]. Macrophages were present in both capillary tufts and cellular crescents as identified by CD68? cells on

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immunoperoxidase labeling. IL-1 activity was greater in the supernatants from cultured glomerular outgrowths of patients with RPGN than in those from rejected renal allografts and glomeruli isolated from the normal tissue. The prominent feature of the glomerular outgrowth of the glomeruli in the RPGN patients was the presence of large numbers of macrophages, which were not present in cultured control glomeruli. These findings indicate that the immunoregulatory aberration in patients with RPGN may in part be due to IL-1 production by activated glomerular macrophages [40]. Some investigations of delayed-type hypersensitivity (DTH) reactions in the glomeruli of patients with pauciimmune crescentic GN suggest the possibility of a role for cell-mediated immunity in this form of GN [81]. An exploration of the mechanisms of macrophage influx in crescent formation has focused on animal models of anti-GBM GN [82]. The existence of CD4? T cells, macrophages, and fibrin in crescentic GN suggests the participation in DTH-like cell-mediated immunity in the progression of inflamed glomeruli [82, 83]. Macrophage infiltration into the crescents is thought to be part of a DTH-like response. The precise mechanisms by which sensitized T cells and macrophages recognize antigens within the inflamed glomeruli remain unclear. It is hypothesized that renal DCs and/or macrophages may take part in the antigen recognition process; however, the implication of parenchymal cells such as mesangial and tubular epithelial cells to express MHC II raises the possibility of their close participation in secondary antigen recognition and induction of the cell-mediated effecter reaction in the progression of crescentic GN. The above observations prompted us to investigate the role of MIF in human GN [84]. We and others have suggested that the cytokine MIF is a key modifier of the DTH response and a potential activator of macrophage functions outside or within the kidney [84, 85]. Macrophages also are a principal source of procoagulant activity in crescent formation [86], and the blockade of tissue factor reduced the crescent formation in rabbit anti-GBM GN [86].

Macrophage migration inhibitory factor in human kidney disease The pathogenesis of IgAN is still unknown. Its etiology is complex and seems to be multifunctional. Cytokines play a crucial role in the development and perpetuation of IgAN [87]. The available data suggest that a disturbed balance of pro- and anti-inflammatory cytokines is an important mechanism of chronic inflammation in IgAN [88, 89]. Although several lines of research have implicated MIF in the pathogenesis of experimental GN [85, 90], very little is

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known of the role that MIFs may play in the pathological complication of human IgAN. As far as we are aware, there has been no previous attempt to measure urinary MIF in a patient population of adults with IgAN [91]. Our data provide evidence that urinary excretion of MIF is increased in IgAN patients with active renal lesions. We found that there was a significant correlation between the severity of intraglomerular and interstitial macrophage numbers and the concentration of urinary MIF. We demonstrated that the levels of urinary MIF had been increased 2 weeks before the flaring of disease activity in the retrospective study, reflecting the clinicopathological activity of the disease [91]. These findings suggest the possibility that MIF takes part in the mechanisms of inflammation and immunological events in the human kidney. Macrophages play a critical role in the development and perpetuation of focal glomerular sclerosis (FGS) [41, 92]. The levels of MIF in the urine of FGS patients were significantly higher than those of the normal controls and patients with minimal-change nephrotic syndrome and membranous nephropathy [93]. In the study, attention also focused on the relationship between urinary MIF levels and pathological features. Among the patients with FGS, urinary MIF levels were significantly correlated with the grade of mesangial matrix increase and that of interstitial fibrosis. There was also a significant correlation between urinary MIF levels and the number of both intraglomerular and interstitial macrophages. In the longitudinal testing, the daily urinary excretion of MIF decreased in parallel with the disease activity, suggesting that the urinary amount of MIF reflects an involvement in the disease process of FGS. We have also examined eight FGS patients who did not respond to steroid therapy [93]. The levels of urinary MIF tended to increase when they did not respond to steroid therapy. Finally, the patients developed steroid-resistant nephrotic syndrome within the following 8 months. These findings suggest that urinary MIF may be useful as a marker of steroid-resistant nephrotic syndrome. In summary, we first found that urinary MIF levels increased in patients with FGS and reflected the clinicopathological characteristics of the disease. Further studies will be required to identify MIF-producing cells and the degradation pathway of MIF in human kidney disease.

Interleukin-17 in IgA nephropathy patients The monocyte/macrophage has been proposed to play an important role in the pathogenesis of disease progression in IgAN [44]. IL-17 is a cytokine produced by CD4? activated memory T cells [94, 95], is an important activator of pro-inflammatory cytokine production by monocytes/macrophages [96], and provides an early switch in the

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differentiation of monocytes. Hence, IL-17 seems a soluble factor by which T cells induce or contribute to inflammation [94–96]. In addition, IL-17 has the ability to stimulate IL-8 production in both epithelial cells and macrophages [97], raising the possibility that this cytokine may play an important role in the recruitment of inflammatory cells. IL-17 has been documented and implicated in the pathogenesis of immune-mediated diseases, such as rheumatoid arthritis, multiple sclerosis, and psoriasis [98]. Antonysamy et al. [99] reported a role of IL-17 in organ allograft rejection and promotion in the functional differentiation of DCs progenitors. Furthermore, it was reported that IL-17 mRNA and protein were detected within kidneys undergoing allograft rejection [100]. As already mentioned, IL-17 is a novel immunoregulatory cytokine involved in inflammatory and immune responses, since it may augment renal inflammatory responses [100–102]. Our data reported here provide direct evidence of a stimulatory effect of IL-17 on the production of proinflammatory cytokines such as IL-1b and TNF-a by monocytes/macrophages in IgAN patients in vitro [101]. Our results also showed that IL-10 blocked the IL-17stimulated production of proinflammatory cytokines by peripheral blood monocytes [101]. IL-10 acts as a general inhibitor of proliferative and cytokine responses of both Th1 and Th2 cells in vitro and in vivo [103]. The immunosuppressive potency of IL-10 depends on the timing of IL-10 and IL-10 receptor expression. It is therefore possible that in IgAN patients IL-10 may exert its effect via the inhibition of IL-17 synthesis by helper T cells present in the mononuclear cell culture system. It may also act independently of monocyte-T cell interactions and inhibit pro-inflammatory cytokine production by monocytes, or it may directly inhibit the monocyte/macrophage function in IgAN patients. The findings may serve as a basis to understand and further analyze IL-17-mediated mechanisms of immunomodulation in IgAN patients. This may be related to T cell interactions with APCs (macrophages, DCs, and so forth) outside or within the kidney. Indeed, TNF-a, which is involved in various inflammatory processes, was detected at high levels in IgAN patients [104]. We have shown before that 24-h urinary IL-17 excretion is increased in states of nephrotic syndrome and normalizes following remission of nephrotic syndrome [102]. Collectively, these results suggest that IL-17 could be a novel target for therapeutic intervention in an immune-mediated renal injury.

Conclusion In this review, we summarized the current knowledge about DCs and macrophages and explored their roles in the

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different mechanisms of renal inflammation. We highlighted the recent advances in the role of their cells in the etiology and progression of kidney disease. We hope that their accumulating findings may contribute to the development of a new stratagem for this disease in the near future. If this promise is realized, it may result in novel therapeutic strategies for the control of acute and chronic renal injury in which DCs and macrophages are the primary participants. Acknowledgments This study was supported in part by the Nihon University Multidisciplinary Research Grant for 2009. The excellent secretarial assistance of Ms. Aika Yanase and Ms. Emi Seki is gratefully acknowledged.

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