Journal of Immunology Research

Journal of Immunology Research / 2019 / Article
Special Issue

Natural Immunomodulators 2018

View this Special Issue

Review Article | Open Access

Volume 2019 |Article ID 5763430 | 11 pages | https://doi.org/10.1155/2019/5763430

The Evolving Roles of Macrophages in Organ Transplantation

Academic Editor: Kurt Zänker
Received21 Dec 2018
Accepted14 Mar 2019
Published24 Apr 2019

Abstract

Organ transplantation is a life-saving strategy for patients with end-stage organ failure. Over the past few decades, organ transplantation has achieved an excellent success in short-term survival but only a marginal improvement in long-term graft outcomes. The pathophysiology of graft loss is multifactorial and remains incompletely defined. However, emerging evidence suggests macrophages as crucial mediators of acute and chronic allograft immunopathology. In this process, macrophage-mediated mobilization of first-line defenses, particularly phagocytosis and the release of acute inflammatory mediators, is important, but macrophages also launch adaptive alloimmune reactions against grafts through antigen processing and presentation, as well as providing costimulation. Additionally, crosstalk with other immune cells and graft endothelial cells causes tissue damage or fibrosis in transplanted organs, contributing to graft loss or tolerance resistance. However, some macrophages function as regulatory cells that are capable of suppressing allogeneic T cells, inhibiting DC maturation, inducing the differentiation of Tregs, and subsequently promoting transplant tolerance. This functional diversity of macrophages in organ transplantation is consistent with their heterogeneity. Although our knowledge of the detrimental or beneficial effects of macrophages on transplants has exponentially increased, the exact mechanisms controlling macrophage functions are not yet completely understood. Here, we review recent advances in our understanding of the multifaceted nature of macrophages, focusing on their evolving roles in organ transplantation and the mechanisms involved in their activation and function in allograft transplantation. We also discuss potential therapeutic options and opportunities to target macrophage to improve the outcomes of transplant recipients.

1. Introduction

Organ transplantation has been a life-saving strategy for patients with end-stage organ failure. However, allografts have been reported to induce alloimmunity and result in graft loss without immunosuppression [1]. In essence, this complicated immunopathology is a multifactorial process involving adaptive and innate immunity. Following numerous advances in immunosuppressants targeting adaptive immune cells, short-term graft survival has achieved tremendous success, with one-year total survival rate exceeding 80% [2]. Nonetheless, this huge success has not translated into long-term benefits, as most grafts are lost over time [3, 4]. Thus, current immunotherapeutic strategies targeting adaptive immune cells display limited effectiveness in promoting long-term graft survival, and researchers have expressed doubt regarding the exclusive role of adaptive immune cells in mediating allograft rejection. Actually, emerging studies suggest that both adaptive immune cells and innate immune cells participate in transplant rejection [57]. Moreover, graft rejection in immunosuppressed patients emphasizes the key role of innate immune cells in graft rejection, including dendritic cells (DCs) [8], macrophages [9, 10], natural killer (NK) cells [11], and mast cells [12].

Tissue macrophages comprise tissue-resident macrophages and recruited monocyte-derived macrophages, both of which play key roles in innate immunity. Macrophages are crucial mediators of transplant immunopathology. Although macrophages mobilize first-line defenses against pathogens and launch adaptive immunity in the form of antigen-presenting cells (APCs) to protect against infection, macrophages also attack allografts as a foreign entity and contribute to graft loss through a similar mechanism [13, 14]. In contrast, in certain preclinical studies and clinical trials, some macrophage subsets have been reported to function as regulatory cells, and adoptive transfer of these macrophages significantly prolongs graft survival. Thus, macrophages have diverse and highly complex roles within allografts, and their various impacts on transplant outcomes reflect the need to reassess the roles of various types of macrophages in organ transplantation.

Emerging evidence reveals the involvement of macrophages in organ transplantation. In mouse transplant models, monocyte cells are capable of recognizing allogeneic nonself antigens independent of lymphoid cells and play crucial roles in triggering alloimmunity and graft rejection [6, 15, 16]. Furthermore, licensed macrophages reject allograft cells via phagocytosis in presensitized models [14]. Deletion or inhibition of macrophages can attenuate graft injury and prolong graft survival [17]. Consistent with the results from animal studies, clinical studies also identified a positive correlation between macrophages and allotransplant rejection [1823]. Additionally, antibody-mediated rejection is characterized by the infiltration of monocytes and macrophages [24, 25]. Macrophage accumulation is even considered as a predictor of death-censored graft failure and a potential diagnostic marker of transplant rejection [26]. Additionally, in heart transplant recipients, macrophages are recognized as one of histological diagnostic criteria [24, 27]. Furthermore, recent studies identified a subset of macrophages that suppress allogeneic T cell proliferation and inhibit DC maturation [28, 29]. Meanwhile, adoptive transfer of these macrophages promotes graft survival and minimizes immunosuppression [28, 30, 31]. The bulk of evidence has kindled great interest in the role of innate immune cells in transplantation, which leads to advances in our understanding of the roles of macrophages in organ transplant.

In this review, we provide a comprehensive update on recent advances in determining the roles of macrophages in organ transplantation, including rejection and transplant tolerance. We also discuss the underlying mechanisms of macrophage activation and function within allografts. We conclude by highlighting a new perspective on therapeutic strategies, as macrophage subsets can potentially be manipulated to control allograft rejection and even contribute to immune tolerance.

2. Macrophage Immunobiology

Macrophages are phagocytic innate immune cells that are crucial components in host defense and tissue homeostasis mechanisms. Macrophages in the tissue comprise tissue-resident macrophages and recruited monocyte-derived macrophages. Fate-mapping studies indicated that macrophages are mainly derived from embryonic progenitors in steady-state tissues rather than adult hematopoietic progenitors. However, macrophage fate depends on the organ type, and the relative contribution is altered in different settings. Notably, macrophages are extremely dynamic and highly plastic, as a variety of environmental stimuli alter either the activation status or function of macrophages. Epigenetic and transcriptomic analyses revealed a critical role for the tissue microenvironment in shaping the tissue macrophage enhancer landscape and determining cell identity [32, 33]. Tissue macrophages, with many tissue-specific functions, are shaped by the surrounding microenvironment and in turn are responsible for maintaining tissue homeostasis [34]. In addition, macrophages originating from different tissues show distinct phenotypes and functions, even under the same polarization conditions [35, 36]. Although transcriptional regulation and epigenetic modifications of macrophage subsets are reasonably well studied, researchers have not clearly determined whether humans and mice exhibit the same macrophage populations and functions.

Traditionally, based on stimulation in vitro, macrophages are oversimplified as M1 (stimulated with interferon gamma/lipopolysaccharide (IFN-γ/LPS)) and M2 macrophages (stimulated with interleukin-4/interleukin-13 (IL-4/IL-13)) [3739]. Although this categorization ignores the diversity and complexity of tissue macrophages in vivo, no widely accepted refined classification exists, and we will continue to use this approach in this review.

M1 macrophages, also called “classically activated macrophages,” tend to be proinflammatory cells that secrete proinflammatory cytokines, such as IL-1, IL-6, tumor necrosis factor-α (TNF-α), and IL-23. M1 macrophages are also capable of eradicating bacterial, fungal, or viral infections. They are polarized following stimulation with IFN-γ, LPS, TNF-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF) and the engagement of Toll-like receptors (TLR) by microbial products or DAMPs (Figure 1). This subset is characterized by the high expression of inducible nitric oxide synthase (iNOS). Although M1 macrophages contribute to anti-infection responses, their sustained activation, particularly under sterile inflammatory conditions, will lead to tissue injury.

M2 macrophages, which are also described as “alternative activated macrophages,” possess anti-inflammatory functions and are capable of facilitating wound healing, angiogenesis, phagocytosis, fibrosis, and the resolution of inflammation. The polarization of this macrophage subset is induced by IL-4/IL-13. These cytokines activate the JAK-STAT6 pathway, driving the transcription of M2-associated genes, such as Arg1, Mrc1, Retnla, and Chil3 (Figure 1). High expression of numerous growth factors, including platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factors (VEGF-α), is one of the distinct characters of M2 macrophages. Additionally, M2 macrophages also express mannose receptor 1 (also called CD206), arginase-1 (Arg1), and transforming growth factor beta 1 (TGF-β1) at high levels.

3. Features of Donor and Graft-Infiltrating Recipient Macrophages

Based on their origins, the macrophages identified in solid organ transplants are divided into donor-resident macrophages, which are transferred to the recipient at the time of transplantation, and recipient monocytes that are recruited into the transplanted organ.

3.1. Donor Macrophages

Donor macrophages, which are present in the organ before transplantation, are donor organ tissue-resident macrophages. In the steady state, tissue-resident macrophages are normal components of the tissue stroma, forming part of the first line of defense against invading pathogens. Meanwhile, tissue-resident macrophages are responsible for maintaining tissue homeostasis by phagocytosing necrotic cells and inhibiting inflammatory responses to innocuous stimuli.

Tissue-resident macrophages primarily originate from the yolk sac, the fetal liver, or both tissues; however, some of these cells will be replaced by monocytes derived from adult bone marrow. The relative contributions of these tissue macrophages vary among organ types. For example, kidney-resident macrophages are derived from both yolk sac and hematopoietic progenitors; tissue macrophages in the lung and liver, which are referred to as alveolar macrophages and Kupffer cells, respectively, are mainly derived from the fetal liver and monocytes. Tissue macrophages in the intestine or heart are mainly replaced by adult bone marrow–derived monocytes [40].

Phenotypically, under steady-state conditions, murine tissue-resident macrophages are primarily characterized by the expression of CD11b, F4/80, CD64, CD68, and MerTK and low levels of MHC-II on the cell surface. However, monocyte-derived macrophages are characterized by CD11b, CD209, CD64, and MerTK expression on the cell surface. In humans, tissue-resident macrophages are phenotypically distinguishable and express CD11b, CD64, CD163, CD14, factor XIIIA, and LYVE-1 on the cell surface, while human monocyte-derived macrophages are characterized by CD11b, CD209, CD14, and factor XIIIA expression on the cell surface.

Functionally, under steady-state conditions, tissue-resident macrophages are capable of maintaining peripheral homeostasis by inhibiting T cell activation and proliferation. Brain microglia [41], lung alveolar macrophages [42], Kupffer cells in the liver [43], and lamina propria macrophages [44] exhibit this suppressive function. Additionally, tissue-resident macrophages are thought to be related to the immunogenicity of allograft, as either differences in the origin or subset distribution of the macrophages in the donor tissue may at least partially correlate with the differences in immunogenicity of the transplanted organ.

3.2. Recipient Macrophages

In the graft, IRI following organ harvest and vascular anastomosis triggers the mobilization of mononuclear phagocytes in bone marrow and allograft infiltration [45]. Monocytes and their precursors are recruited from the blood, bone marrow, and spleen to the grafts. The recruitment of these cells is mediated by chemoattractants such as monocyte chemoattractant protein-1 (MCP-1) [46], chemokine (C-C motif) ligand 2 (CCL2) [46], C-C chemokine receptor type 1 (CCR1), chemokine (C-X3-C motif) ligand 1 (CX3CL1) [47], macrophage inflammatory protein-1α (MIP-1α) [48], and C5aR1 [49, 50]. Subsequently, the cells infiltrate the graft, differentiate into macrophages or DCs, and play a crucial role in determining the outcome of transplantation.

Phenotypically, the origins of graft-infiltrating macrophages are difficult to determine based on their phenotypes; however, cell-tracing strategies using CD45.1/CD45.2 or GFP reporter mice have enabled researchers to distinguish between donor and recipient macrophages [51]. Interestingly, a study of sex-mismatched heart transplant patients revealed that CCR2 facilitates the differentiation between donor macrophages and recipient macrophages within an allograft, as CCR2- macrophages belong to a tissue-resident subset while CCR2+ macrophages are derived from monocytes [52]. Moreover, either CSF1R (CD115) or Gr1 facilitates the differentiation between tissue-resident macrophages and monocyte-derived macrophages, as bone marrow Ly6Chi monocytes or the Gr1+ monocyte subset is selectively recruited into injured organs and differentiates into macrophages [53, 54]. However, these phenotypes vary according to the type of organ and differences exist between mouse and human, which is worthy of further investigation.

Functionally, as first responders, interstitial monocyte-derived cells infiltrate allografts within hours [47]. Monocytes trafficking into IRI are regulated by chemokine receptors, such as CCR2 and CX3C chemokine receptor 1 (CX3CR1), as both CCR2-deficient and CX3CR1-deficient mice showed reduced tissue injury. Egress of these cells into an injured organ was observed within 30 minutes following injury and peaked within 24-48 h [47]. This rapid accumulation of monocyte-derived macrophages is the first step in a conventional reaction that causes further tissue damage.

4. Macrophages in Acute Rejection

With the extensive use of immunosuppression, acute rejection is no longer a major hurdle in transplantation; however, the mechanism of acute rejection remains incompletely understood.

Accumulating evidence has suggested a pivotal role for macrophages in acute rejection. Macrophages are involved in IRI, the alloimmune response, and acute graft rejection. Based on human biopsy data, macrophages account for 38–60% of graft-infiltrating leukocytes during acute rejection [5558]. Consistent with the increased macrophage infiltration, the levels of both chemotactic factors responsible for monocyte recruitment and macrophage colony-stimulating factor (M-CSF) responsible for macrophage proliferation are increased within allografts during the postreperfusion period and acute rejection [59]. Moreover, a whole-genome transcriptome analysis of biopsy samples identified an inflammatory macrophage-associated 3-gene signature that is upregulated during acute rejection and positively correlated with the extent of subclinical graft injury [60]. In contrast, macrophage depletion attenuates graft injury and decreases inflammation in acute rejection models [61, 62]. Macrophage infiltration is even suggested to function as potential biomarker of rejection, graft function, and graft survival. Thus, macrophages represent as an important cell type that mediates acute allograft rejection.

Both IRI and acute rejection models revealed a role for macrophages in tissue injury. Macrophage infiltration occurs rapidly following reperfusion during transplantation. Once in the transplanted organ, activated macrophages produce large amounts of proinflammatory cytokines that damage the tissue, such as IL-1, IL-12, IL-18, IL-6, IL-23, TNF-α, and IFN-γ [57, 63]. Among these proinflammatory cytokines, TNF-α is capable of promoting tubular apoptosis after kidney injury, as neutralization of TNF-α leads to decreased renal IRI [64]. Similarly, IL-12 contributes to IRI, as IL-12 deletion exerts a protective effect on IRI [65]. These cytokines promote inflammation and tissue injury through divergent pathways; however, further study is required to determine the association between the cytokine source and cytokine function in mediating IRI and acute graft injury. In addition to cytokine-mediated effects, infiltrated macrophages also lead to allograft tissue damage by producing reactive oxygen species (ROS) and reactive nitrogen species (RNS), which subsequently promote acute rejection [6669]. Mechanistically, interactions between RNS and ROS promote the generation of cytotoxic peroxynitrites, causing lipid peroxidation. Thus, macrophages are well-equipped effector cells that mediate acute graft injury.

Macrophages are also capable of mediating transplant rejection via activating adaptive alloimmune responses. Both donor macrophages and recipient macrophages, which function as APCs, exert substantial effects on alloimmune responses. Mechanistically, alloimmune T cells are activated following an interaction of their T cell receptors with intact allogeneic MHC molecules on donor cells or donor peptides presented by self-MHC molecules on recipient APCs, or with recipient APCs with intact MHCs transferred from donor APCs. Furthermore, macrophages provide costimulatory signals to facilitate and amplify T cell activation, as costimulatory molecules are expressed at high levels on the macrophage surface. Despite the significant progress in determining the roles of macrophages in tissue injury and organ rejection, the mechanisms by which these macrophages mediate graft loss are not completely understood. Although macrophages play key roles in amplifying T cell-mediated acute rejection, the relative contributions of macrophages and DCs require further study.

5. Macrophages in Chronic Rejection

Chronic rejection has become a major cause of allograft loss in the clinical setting. The features of chronic rejection include vascular smooth muscle proliferation, neointima formation, damage and atrophy of parenchymal cells, interstitial inflammation and fibrosis, and, finally, vascular occlusion. Based on findings from emerging studies, macrophages are a critical mediator of chronic rejection. Chronically rejecting allografts are characterized by the interstitial infiltration of macrophages and T cells [70]. Compared with T cell-mediated acute rejection, the macrophages outnumber T cells in the graft in chronic rejection models and human patients [71, 72]. Increased macrophage infiltration within allografts positively correlates with worse graft outcome [19], and macrophage accumulation even functions as a potential diagnostic marker of graft rejection in restricted transplantation models [24, 27]. In addition, impaired macrophage recruitment into grafts mediated by the pharmacological blockade of RhoA/Rock or deletion of RhoA, which is involved in regulating the actin cytoskeleton, inhibits chronic rejection of heart transplants and prolonged graft survival [73, 74]. Similarly, macrophage depletion after transplantation reduces transplant vasculopathy and prolongs graft survival [7577].

Mechanistically, macrophages likely contribute to chronic rejection by promoting smooth muscle cell proliferation and interstitial fibrosis. These effects are associated with the M2 macrophage subset, which promotes proliferation by secreting a variety of growth factors and exert profibrotic effects. Animal transplant models revealed high levels of M2-associated markers, such as Arg-1, CD206, and Fizz1, on graft-infiltrating macrophages in chronically rejected grafts [75]. Moreover, graft biopsies from patients display a dominant population of M2-polarized macrophages [20, 75]. Furthermore, the accumulation of M2 macrophages correlates with the severity of fibrosis [20, 78]. In contrast, strategic inhibition of graft-infiltrating M2 macrophages with oxidized ATP, whose receptor, P2x7r, is preferentially expressed in M2 macrophages, results in reduced transplant vasculopathy, decreased fibrosis, and prolonged cardiac graft survival [75]. Consistent with these findings, block M2 macrophages by the conditional deletion of mammalian target of rapamycin (mTOR) in macrophages induces long-term graft survival without showing obvious features of chronic rejection [77].

Intriguingly, macrophages also facilitate interstitial fibrosis in chronic allograft injury by undergoing the macrophage-to-myofibroblast transition, which is characterized by the coexpression of macrophage (CD68) and myofibroblast (α-smooth muscle actin (α-SMA)) markers. The macrophage-to-myofibroblast transition was identified in both patients undergoing chronic allograft rejection and a chronic renal allograft injury model. A fate-mapping study using Lyz2-Cre/Rosa26-Tomato mice revealed that myofibroblasts originating from recipient macrophages account for approximately 50% of the myofibroblasts in renal allografts [79]. Functionally, the accumulation of these cells is associated with allograft function and the severity of interstitial fibrosis. Mechanistically, the macrophage-to-myofibroblast transition is regulated by a Smad3-dependent mechanism, as the deletion of Smad3 impairs the macrophage-to-myofibroblast transition and reduces intestinal fibrosis [79].

Additional roles of macrophage in chronic rejection are also emerging. Macrophages have recently been shown to be involved in alloantibody-mediated chronic rejection, particularly in lung transplantation, although the mechanism remains poorly defined. Lung transplant studies revealed a significant role for donor-derived alveolar macrophages (AMs) in the donor-specific antibody- (DSA-) induced inflammatory cascade, which causes bronchiolar obstruction [80, 81]. Adoptive transfer of allogeneic AMs stimulates lung-restricted humoral and cellular autoimmunity and leads to obstructive airway disease of the transplanted lung [80, 81]. Mechanistically, donor AMs respond to a human leukocyte antigen- (HLA-) specific antibody by secreting proinflammatory cytokines. Furthermore, antigen presentation by AMs requires Zbtb7a, as Zbtb7a deletion failed to induce antibody and T cell responses [81]. Thus, AMs are implicated in anti-HLA-induced lung allograft rejection.

6. Macrophages in Graft Tolerance

Although macrophages contribute to allograft rejection through various mechanisms, recent evidence suggested that macrophages are also involved in transplant tolerance, as adoptive transfer of regulatory macrophages (Mregs) induces graft tolerance. Mregs represent a unique macrophage subset that are induced in the presence of M-CSF and IFN-γ and is distinguished from M1 and M2 cells [29]. Functionally, these cells are characterized by suppressive activity and anti-inflammatory properties. T cell proliferation is nonspecifically suppressed by Mregs through the preferential elimination of allogeneic T cells [82]. In mice, these functions are mediated by an iNOS-dependent mechanism, as Nos2-deficient Mregs failed to suppress T cell proliferation [83]. In a murine cardiac transplantation model, adoptive transfer of Mregs dramatically improved cardiac allograft survival in nonimmunosuppressed and fully allogeneic recipients; however, the transfer of Nos2-deficient Mregs failed to prolong allograft survival [83].

Another significant issue is that Mregs also function as critical mediators of graft tolerance. Mregs are characterized by the capability to inhibit CD8+T cell immunity and promote CD4+ forkhead box P3 + (Foxp3+) regulatory T cell (Treg) expansion [84]. This type of suppressive macrophage is required to induce graft tolerance, as the depletion of suppressive macrophages in vivo abrogates allograft tolerance, despite a tolerogenic treatment [84]. Mechanistically, simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 pathways promotes the expression of IL-10, which is essential for Mreg-mediated prolongation of allograft survival [84]. Thus, Mregs play a pivotal role in immunological tolerance and have concomitant therapeutic implications in the clinic.

Similar to mouse Mregs, human Mregs are induced following stimulation with M-CSF and IFN-γ [29, 84, 85]. Phenotypically, human Mregs are characterized by the expression of DHRS9, which is a unique and robust marker of human Mregs but not mouse Mregs [85]. Human Mregs are capable of suppressing the proliferation and activation of allogeneic T cells, as well as depleting allogeneic T cells [29]. Furthermore, human Mregs rapidly induce TIGIT+Foxp3+-induced Tregs and inhibit DC maturation, promoting allograft acceptance [28]. In the transplant acceptance-inducing cell- (TAIC-) I clinical trial, Mreg-based therapy was administered to 12 patients received kidney transplants from deceased donors. No obvious adverse effects or signs of clinical rejection were observed, which prompted the use of Mreg-targeted therapy as a safe and practical therapeutic approach in renal transplantation [31]. Subsequently, the TAIC-II clinical trial, in which 5 patients underwent living-donor kidney transplantation, confirmed the safety of the Mreg-targeted strategy and suggested that TAICs are highly potent in suppressing alloantigen-specific responses and minimizing immunosuppression [30]. In another clinical trial, an Mreg treatment was administered to 2 patients received living-donor kidney transplantation, resulting in stable renal function with very low-dose tacrolimus monotherapy [29]. Both recipients have survived for more than 6 years after transplantation without showing acute or delayed adverse responses and signs of subclinical rejection. Furthermore, another clinical trial of Mregs is currently in progress, which will recruit 16 living donor kidney transplant recipients (clinicaltrials.gov: NCT02085629).

Clearly, all these data highlight the potential effectiveness of macrophage-based therapies in transplantation; however, further studies are warranted to determine the mechanism by which Mregs mediate transplant tolerance, including the safety and stability of Mregs in vivo and the efficacy of Mreg treatments in a wide and variable population.

7. Therapies Targeting Macrophages for Solid Organ Transplant

Current studies identified both the beneficial and detrimental effects of macrophages on various solid organ transplant models. The essential roles of macrophages in transplantation have indicated the therapeutic potential of macrophage-targeted treatment in organ transplantation. Thus, the mechanisms underlying macrophage migration, activation, and action might be potential therapeutic targets. In principle, strategies targeting macrophages in an attempt to prolong graft survival and even graft tolerance include preventing macrophage accumulation within the allograft, manipulating their activation, and inducing suppressive macrophages in favor of inducing tolerance (Figure 2).

7.1. Preventing the Accumulation of Macrophages in Allografts

Investigations in animal transplant models have shown that appropriately timed depletion of macrophages or inhibition of macrophage migration maintains graft function and prolong allograft survival. A carrageenan treatment, which exerted negligible effects upon T, B, or NK cells, depleted 30–80% macrophages within cardiac allografts and led to a 70% reduction in transplant vasculopathy [76]. Conditional deletion of monocytes and macrophages in CD11b-DTR mice effectively prevented macrophage infiltration in murine renal allografts and resulted in reduced acute rejection-related tissue injury [17]. Furthermore, the impaired macrophage migration induced by conditional deletion of RhoA in macrophages reduced transplant vasculopathy and interstitial fibrosis and improved graft survival [73]. Additionally, blockade of CSF-1/CSF-1R signaling seems to be a potential therapeutic approach to selectively mitigate macrophage accumulation in allografts, as it has been tested in animal models and patients [86]. Furthermore, inhibition of chemokine- and chemokine receptor-mediated chemotaxis also displays therapeutic value in blocking monocyte recruitment, as either a CCR5/CXCR3 antagonist or a neutralizing antibody against CX3CR1 suppressed macrophage infiltration and prolonged graft survival [87]. However, the nonselective inhibition of macrophage accumulation requires further investigation, as these treatments might blunt the patient’s ability to control infections and neglect the fact that the function of regulatory macrophages is required for transplant tolerance. More selective approaches that suppress recruitment of macrophages contributing to allograft injury but not those facilitating transplant acceptance are needed.

7.2. Manipulating the Activation of Macrophages

Because of the functional diversity of macrophages involved in graft injury and rejection, strategies manipulating their activation may provide therapeutic value in the clinic. Suppression of the activation of macrophages with detrimental functions in alloimmunity might be an effective therapy. In chronic rejection models, the P2x7R antagonist oATP binds to P2x7R, resulting in impaired M2 polarization and reduced transplant vasculopathy [75]. Additionally, a conditional deficiency of mTOR in macrophages inhibits M2 macrophage activation and prevents allograft rejection via the programmed cell death protein 1/programmed cell death 1 ligand (PD-1/PD-L1) coinhibitory pathway and the expansion of Tregs [77]. Blockade of macrophage-mediated proinflammatory responses might also improve graft survival. The proinflammatory activation of graft-infiltrating macrophages was preferentially inhibited by a short-term treatment with high-density lipoprotein (HDL) nanoparticles loaded with rapamycin (mTORi) and reduced cytokine and lactate production upon restimulation with LPS, suggesting that mTORi-HDL as a possible macrophage-targeted therapy for organ transplantation. In cardiac transplantation models, targeting macrophages with mTORi-HDL markedly prolonged graft survival by reducing the number of graft-infiltrating inflammatory Ly6Chi macrophages and increasing the number of Ly6Clo macrophages [88]. Neutralization of the Fcγ receptor suppresses antigen presentation capability of monocytes and inhibits proinflammatory macrophages, but promotes the activity of immunoregulatory macrophages by upregulating IL-10 [89]. In addition, several immunosuppressive drugs used in current clinical practice, including glucocorticoids, rapamycin inhibitors, and mycophenolate mofetil, also partially exert their therapeutic effects by suppressing proinflammatory macrophages [10]. Although these methods are useful for manipulating the activation of macrophages, more specific approaches without apparent systemic side effects are required. A potential alternative strategy would be to selectively inhibit proinflammatory and alloreactive macrophages within allografts and enhance the function of suppressive macrophages or to repolarize graft-infiltrating macrophages to exert a regulatory function. These strategies are attractive, but further studies are required before they are translated to clinical applications.

7.3. Suppressive Macrophage-Based Approaches

As suppressive macrophages play an essential role in mediating transplant tolerance, the use of suppressive macrophages as therapeutic agents in adoptive transfer displays substantial therapeutic potential in humans. Adoptive transfer of Mregs in animal models produced promising results, as graft survival was dramatically improved. Although clinical trials of Mregs are limited, the results are promising, as both recipients continue to show stable renal function with a very low dose of tacrolimus monotherapy at more than 6 years after adoptive transfer [29]. Indeed, adoptive transfer of suppressive macrophages has several advantages over conventional therapeutic approaches. Suppressive macrophages have the potential to mediate contact-dependent depletion of activated T cells and drive the differentiation of Tregs from naive non-Tregs, thus avoiding the toxicity of general immunosuppressants. Moreover, a suppressive macrophage treatment can reestablish immunological tolerance and exert lasting therapeutic effects on mice. In addition to the adoptive transfer of Mregs, strategies promoting Mreg polarization in vivo via an M-CSF-dependent pathway also represent a novel therapeutic approach for organ transplantation recipients, as neutrophil-derived CSF-1 promotes Mreg polarization and the suppressive functions of graft infiltrating macrophages [90]. Additionally, the induction of Mregs with nanotechnology tools, such as mTORi-HDL, also promotes transplant tolerance, as these macrophages are capable of suppressing alloreactive CD8+ T cell-mediated immunity and enhancing tolerogenic Treg expansion [88]. However, before suppressive macrophage therapy is translated to the clinic, numerous issues must be addressed with human suppressive macrophages, including the efficiency of Mreg induction, stability, and plasticity in vivo.

8. Conclusions

Over the past few years, our understanding of the biology of macrophages in homeostasis and disease has significantly improved. Furthermore, findings from preclinical models of solid organ transplantation and clinical studies reveal the involvement of macrophages in determining transplant outcomes and indicate the therapeutic potential of macrophage-targeted approaches in the clinic. However, the challenge is the heterogeneity of macrophages in vivo, as macrophages are capable of differentiating into phenotypically and functionally distinct subsets, depending on the organ types, the local cytokine milieu, and the crosstalk with other immune cells. Moreover, limited strategies exist to selectively manipulate specific macrophage subsets. Thus, a sufficient number of specific makers must be identified to facilitate the selective targeting of graft-infiltrating macrophage subsets. Although extensive animal studies have revealed the potency and efficacy of macrophage-targeted therapies in organ transplantation, the mechanisms have not defined, and most of them remain unexplored in the clinic.

Obviously, a thorough understanding of macrophage biology is the key to translating macrophage- targeted therapy into clinic practice. Notably, the current categorization schemes do not reflect the diversity and complexity of macrophages in vivo; thus, a consensus classification of macrophage subsets and definitions for novel subsets are urgently needed. Fortunately, studies employing genomics, transcriptomics, and proteomics technologies will considerably facilitate the definition of the heterogeneity and diversity of macrophages in humans and will enable the development of selective strategies that target graft-infiltrating macrophages to improve the outcomes of transplant recipients.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Acknowledgments

This project was supported by the National Natural Science Foundation of China (81771722 and 81700658). We are grateful for colleagues at Organ Transplantation Center for their critical reading of the manuscript.

References

  1. P. Libby and J. S. Pober, “Chronic rejection,” Immunity, vol. 14, no. 4, pp. 387–397, 2001. View at: Publisher Site | Google Scholar
  2. J. Stehlik, M. R. Mehra, S. C. Sweet et al., “The International Society for Heart and Lung Transplantation registries in the era of big data with global reach,” The Journal of Heart and Lung Transplantation, vol. 34, no. 10, pp. 1225–1232, 2015. View at: Publisher Site | Google Scholar
  3. C. Martin-Gandul, N. J. Mueller, M. Pascual, and O. Manuel, “The impact of infection on chronic allograft dysfunction and allograft survival after solid organ transplantation,” American Journal of Transplantation, vol. 15, no. 12, pp. 3024–3040, 2015. View at: Publisher Site | Google Scholar
  4. B. J. Nankivell and D. R. Kuypers, “Diagnosis and prevention of chronic kidney allograft loss,” The Lancet, vol. 378, no. 9800, pp. 1428–1437, 2011. View at: Publisher Site | Google Scholar
  5. S. P. Murphy, P. M. Porrett, and L. A. Turka, “Innate immunity in transplant tolerance and rejection,” Immunological Reviews, vol. 241, no. 1, pp. 39–48, 2011. View at: Publisher Site | Google Scholar
  6. F. G. Lakkis and X. C. Li, “Innate allorecognition by monocytic cells and its role in graft rejection,” American Journal of Transplantation, vol. 18, no. 2, pp. 289–292, 2018. View at: Publisher Site | Google Scholar
  7. M. H. Oberbarnscheidt and F. G. Lakkis, “Innate allorecognition,” Immunological Reviews, vol. 258, no. 1, pp. 145–149, 2014. View at: Publisher Site | Google Scholar
  8. A. E. Morelli and A. W. Thomson, “Tolerogenic dendritic cells and the quest for transplant tolerance,” Nature Reviews Immunology, vol. 7, no. 8, pp. 610–621, 2007. View at: Publisher Site | Google Scholar
  9. Y. Liu, M. Kloc, and X. C. Li, “Macrophages as effectors of acute and chronic allograft injury,” Current Transplantation Reports, vol. 3, no. 4, pp. 303–312, 2016. View at: Publisher Site | Google Scholar
  10. T. P. P. van den Bosch, N. M. Kannegieter, D. A. Hesselink, C. C. Baan, and A. T. Rowshani, “Targeting the monocyte–macrophage lineage in solid organ transplantation,” Frontiers in Immunology, vol. 8, p. 153, 2017. View at: Publisher Site | Google Scholar
  11. G. Yu, X. Xu, M. D. Vu, E. D. Kilpatrick, and X. C. Li, “NK cells promote transplant tolerance by killing donor antigen-presenting cells,” Journal of Experimental Medicine, vol. 203, no. 8, pp. 1851–1858, 2006. View at: Publisher Site | Google Scholar
  12. L. F. Lu, E. F. Lind, D. C. Gondek et al., “Mast cells are essential intermediaries in regulatory T-cell tolerance,” Nature, vol. 442, no. 7106, pp. 997–1002, 2006. View at: Publisher Site | Google Scholar
  13. H. Dai, A. J. Friday, K. I. Abou-Daya et al., “Donor SIRPα polymorphism modulates the innate immune response to allogeneic grafts,” Science Immunology, vol. 2, no. 12, article eaam6202, 2017. View at: Publisher Site | Google Scholar
  14. W. Liu, X. Xiao, G. Demirci, J. Madsen, and X. C. Li, “Innate NK cells and macrophages recognize and reject allogeneic nonself in vivo via different mechanisms,” The Journal of Immunology, vol. 188, no. 6, pp. 2703–2711, 2012. View at: Publisher Site | Google Scholar
  15. M. H. Oberbarnscheidt, Q. Zeng, Q. Li et al., “Non-self recognition by monocytes initiates allograft rejection,” The Journal of Clinical Investigation, vol. 124, no. 8, pp. 3579–3589, 2014. View at: Publisher Site | Google Scholar
  16. D. Zecher, N. van Rooijen, D. M. Rothstein, W. D. Shlomchik, and F. G. Lakkis, “An innate response to allogeneic nonself mediated by monocytes,” The Journal of Immunology, vol. 183, no. 12, pp. 7810–7816, 2009. View at: Publisher Site | Google Scholar
  17. F. Qi, A. Adair, D. Ferenbach et al., “Depletion of cells of monocyte lineage prevents loss of renal microvasculature in murine kidney transplantation,” Transplantation, vol. 86, no. 9, pp. 1267–1274, 2008. View at: Publisher Site | Google Scholar
  18. J. H. Brasen, A. Khalifa, J. Schmitz et al., “Macrophage density in early surveillance biopsies predicts future renal transplant function,” Kidney International, vol. 92, no. 2, pp. 479–489, 2017. View at: Publisher Site | Google Scholar
  19. T. Bergler, B. Jung, F. Bourier et al., “Infiltration of macrophages correlates with severity of allograft rejection and outcome in human kidney transplantation,” PLoS One, vol. 11, no. 6, article e0156900, 2016. View at: Publisher Site | Google Scholar
  20. D. Toki, W. Zhang, K. L. M. Hor et al., “The role of macrophages in the development of human renal allograft fibrosis in the first year after transplantation,” American Journal of Transplantation, vol. 14, no. 9, pp. 2126–2136, 2014. View at: Publisher Site | Google Scholar
  21. K. J. Tinckam, O. Djurdjev, and A. B. Magil, “Glomerular monocytes predict worse outcomes after acute renal allograft rejection independent of C4d status,” Kidney International, vol. 68, no. 4, pp. 1866–1874, 2005. View at: Publisher Site | Google Scholar
  22. P. J. Matheson, I. D. Dittmer, B. W. Beaumont, M. J. Merrilees, and H. L. Pilmore, “The macrophage is the predominant inflammatory cell in renal allograft intimal arteritis,” Transplantation, vol. 79, no. 12, pp. 1658–1662, 2005. View at: Publisher Site | Google Scholar
  23. W. W. Hancock, N. M. Thomson, and R. C. Atkins, “Composition of interstitial cellular infiltrate identified by monoclonal antibodies in renal biopsies of rejecting human renal allografts,” Transplantation, vol. 35, no. 5, pp. 458–462, 1983. View at: Publisher Site | Google Scholar
  24. L. Xu, J. Collins, C. Drachenberg, D. Kukuruga, and A. Burke, “Increased macrophage density of cardiac allograft biopsies is associated with antibody-mediated rejection and alloantibodies to HLA antigens,” Clinical Transplantation, vol. 28, no. 5, pp. 554–560, 2014. View at: Publisher Site | Google Scholar
  25. S. Salehi, R. A. Sosa, Y. P. Jin et al., “Outside-in HLA class I signaling regulates ICAM-1 clustering and endothelial cell-monocyte interactions via mTOR in transplant antibody-mediated rejection,” American Journal of Transplantation, vol. 18, no. 5, pp. 1096–1109, 2018. View at: Publisher Site | Google Scholar
  26. P. C. Grimm, R. McKenna, P. Nickerson et al., “Clinical rejection is distinguished from subclinical rejection by increased infiltration by a population of activated macrophages,” Journal of the American Society of Nephrology, vol. 10, no. 7, pp. 1582–1589, 1999. View at: Google Scholar
  27. G. A. Fishbein and M. C. Fishbein, “Morphologic and immunohistochemical findings in antibody-mediated rejection of the cardiac allograft,” Human Immunology, vol. 73, no. 12, pp. 1213–1217, 2012. View at: Publisher Site | Google Scholar
  28. P. Riquelme, J. Haarer, A. Kammler et al., “TIGIT+ iTregs elicited by human regulatory macrophages control T cell immunity,” Nature Communications, vol. 9, no. 1, p. 2858, 2018. View at: Publisher Site | Google Scholar
  29. J. A. Hutchinson, P. Riquelme, B. Sawitzki et al., “Cutting edge: immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients,” The Journal of Immunology, vol. 187, no. 5, pp. 2072–2078, 2011. View at: Publisher Site | Google Scholar
  30. J. A. Hutchinson, B. G. Brem-Exner, P. Riquelme et al., “A cell-based approach to the minimization of immunosuppression in renal transplantation,” Transplant International, vol. 21, no. 8, pp. 742–754, 2008. View at: Publisher Site | Google Scholar
  31. J. A. Hutchinson, P. Riquelme, B. G. Brem-Exner et al., “Transplant acceptance-inducing cells as an immune-conditioning therapy in renal transplantation,” Transplant International, vol. 21, no. 8, pp. 728–741, 2008. View at: Publisher Site | Google Scholar
  32. D. Gosselin, V. M. Link, C. E. Romanoski et al., “Environment drives selection and function of enhancers controlling tissue-specific macrophage identities,” Cell, vol. 159, no. 6, pp. 1327–1340, 2014. View at: Publisher Site | Google Scholar
  33. Y. Lavin, D. Winter, R. Blecher-Gonen et al., “Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment,” Cell, vol. 159, no. 6, pp. 1312–1326, 2014. View at: Publisher Site | Google Scholar
  34. Y. Okabe and R. Medzhitov, “Tissue biology perspective on macrophages,” Nature Immunology, vol. 17, no. 1, pp. 9–17, 2016. View at: Publisher Site | Google Scholar
  35. U. M. Gundra, N. M. Girgis, D. Ruckerl et al., “Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct,” Blood, vol. 123, no. 20, pp. e110–e122, 2014. View at: Publisher Site | Google Scholar
  36. K. M. Vannella, L. Barron, L. A. Borthwick et al., “Incomplete deletion of IL-4Rα by LysMCre reveals distinct subsets of M2 macrophages controlling inflammation and fibrosis in chronic schistosomiasis,” PLoS Pathogens, vol. 10, no. 9, article e1004372, 2014. View at: Publisher Site | Google Scholar
  37. C. D. Mills, K. Kincaid, J. M. Alt, M. J. Heilman, and A. M. Hill, “M-1/M-2 macrophages and the Th1/Th2 paradigm,” The Journal of Immunology, vol. 164, no. 12, pp. 6166–6173, 2000. View at: Publisher Site | Google Scholar
  38. M. Munder, K. Eichmann, and M. Modolell, “Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype,” The Journal of Immunology, vol. 160, no. 11, pp. 5347–5354, 1998. View at: Google Scholar
  39. M. Munder, K. Eichmann, J. M. Moran, F. Centeno, G. Soler, and M. Modolell, “Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells,” The Journal of Immunology, vol. 163, no. 7, pp. 3771–3777, 1999. View at: Google Scholar
  40. F. Ginhoux and M. Guilliams, “Tissue-resident macrophage ontogeny and homeostasis,” Immunity, vol. 44, no. 3, pp. 439–449, 2016. View at: Publisher Site | Google Scholar
  41. B. Bai, W. Song, Y. Ji et al., “Microglia and microglia-like cell differentiated from DC inhibit CD4 T cell proliferation,” PLoS One, vol. 4, no. 11, article e7869, 2009. View at: Publisher Site | Google Scholar
  42. P. Soroosh, T. A. Doherty, W. Duan et al., “Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance,” Journal of Experimental Medicine, vol. 210, no. 4, pp. 775–788, 2013. View at: Publisher Site | Google Scholar
  43. Q. You, L. Cheng, R. M. Kedl, and C. Ju, “Mechanism of T cell tolerance induction by murine hepatic Kupffer cells,” Hepatology, vol. 48, no. 3, pp. 978–990, 2008. View at: Publisher Site | Google Scholar
  44. E. Zigmond, B. Bernshtein, G. Friedlander et al., “Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis,” Immunity, vol. 40, no. 5, pp. 720–733, 2014. View at: Publisher Site | Google Scholar
  45. M. R. Garcia, L. Ledgerwood, Y. Yang et al., “Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice,” The Journal of Clinical Investigation, vol. 120, no. 7, pp. 2486–2496, 2010. View at: Publisher Site | Google Scholar
  46. G. Grandaliano, L. Gesualdo, E. Ranieri, R. Monno, G. Stallone, and F. P. Schena, “Monocyte chemotactic peptide-1 expression and monocyte infiltration in acute renal transplant rejection,” Transplantation, vol. 63, no. 3, pp. 414–420, 1997. View at: Publisher Site | Google Scholar
  47. L. Li, L. Huang, S. S. J. Sung et al., “The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia–reperfusion injury,” Kidney International, vol. 74, no. 12, pp. 1526–1537, 2008. View at: Publisher Site | Google Scholar
  48. V. Grau, D. Gemsa, B. Steiniger, and H. Garn, “Chemokine expression during acute rejection of rat kidneys,” Scandinavian Journal of Immunology, vol. 51, no. 5, pp. 435–440, 2000. View at: Publisher Site | Google Scholar
  49. I. Llaudo, M. Fribourg, M. E. Medof, P. Conde, J. Ochando, and P. S. Heeger, “C5aR1 regulates migration of suppressive myeloid cells required for costimulatory blockade-induced murine allograft survival,” American Journal of Transplantation, vol. 19, no. 3, pp. 633–645, 2019. View at: Publisher Site | Google Scholar
  50. P. Riquelme, E. K. Geissler, and J. A. Hutchinson, “C5aR1 governs Mreg migration, development, and function,” American Journal of Transplantation, vol. 19, no. 3, pp. 619–621, 2019. View at: Publisher Site | Google Scholar
  51. A. Schridde, C. C. Bain, J. U. Mayer et al., “Tissue-specific differentiation of colonic macrophages requires TGFβ receptor-mediated signaling,” Mucosal Immunology, vol. 10, no. 6, pp. 1387–1399, 2017. View at: Publisher Site | Google Scholar
  52. G. Bajpai, C. Schneider, N. Wong et al., “The human heart contains distinct macrophage subsets with divergent origins and functions,” Nature Medicine, vol. 24, no. 8, pp. 1234–1245, 2018. View at: Publisher Site | Google Scholar
  53. S. L. Lin, A. P. Castano, B. T. Nowlin, M. L. Lupher, and J. S. Duffield, “Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations,” The Journal of Immunology, vol. 183, no. 10, pp. 6733–6743, 2009. View at: Publisher Site | Google Scholar
  54. K. R. Karlmark, R. Weiskirchen, H. W. Zimmermann et al., “Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis,” Hepatology, vol. 50, no. 1, pp. 261–274, 2009. View at: Publisher Site | Google Scholar
  55. L. Brent, J. Brown, and P. B. Medawar, “Skin transplantation immunity in relation to hypersensitivity,” The Lancet, vol. 272, no. 7046, pp. 561–564, 1958. View at: Publisher Site | Google Scholar
  56. T. Abe, C. A. Su, S. Iida et al., “Graft-derived CCL2 increases graft injury during antibody-mediated rejection of cardiac allografts,” American Journal of Transplantation, vol. 14, no. 8, pp. 1753–1764, 2014. View at: Publisher Site | Google Scholar
  57. A. T. Rowshani and E. J. F. Vereyken, “The role of macrophage lineage cells in kidney graft rejection and survival,” Transplantation Journal, vol. 94, no. 4, pp. 309–318, 2012. View at: Publisher Site | Google Scholar
  58. A. I. Gomaa, N. A. Ehsan, A. A. Elrefaei, M. M. Sultan, and M. M. Elsabaawy, “The role of monocyte/macrophage and CXCR3 in differentiation between recurrent hepatitis C and acute cellular rejection postliver transplantation,” Journal of Immunology Research, vol. 2018, Article ID 2726939, 7 pages, 2018. View at: Publisher Site | Google Scholar
  59. K. A. Singh, R. L. Kampen, S. C. Hoffmann, S. M. Eldaif, and A. D. Kirk, “Renal epithelial cell-derived monocyte colony stimulating factor as a local informant of renal injury and means of monocyte activation,” Transplant International, vol. 22, no. 7, pp. 730–737, 2009. View at: Publisher Site | Google Scholar
  60. T. D. Azad, M. Donato, L. Heylen et al., “Inflammatory macrophage–associated 3-gene signature predicts subclinical allograft injury and graft survival,” JCI Insight, vol. 3, no. 2, 2018. View at: Publisher Site | Google Scholar
  61. Y. Tsushima, J. H. Jang, Y. Yamada et al., “The depletion of donor macrophages reduces ischaemia-reperfusion injury after mouse lung transplantation,” European Journal of Cardio-Thoracic Surgery, vol. 45, no. 4, pp. 703–709, 2014. View at: Publisher Site | Google Scholar
  62. S. Epelman, K. J. Lavine, A. E. Beaudin et al., “Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation,” Immunity, vol. 40, no. 1, pp. 91–104, 2014. View at: Publisher Site | Google Scholar
  63. X. Liu, H. Cao, J. Li et al., “Autophagy induced by DAMPs facilitates the inflammation response in lungs undergoing ischemia-reperfusion injury through promoting TRAF6 ubiquitination,” Cell Death & Differentiation, vol. 24, no. 4, pp. 683–693, 2017. View at: Publisher Site | Google Scholar
  64. J. D. Eason, S. Wee, T. Kawai et al., “Inhibition of the effects of TNF in renal allograft recipients using recombinant human dimeric tumor necrosis factor receptors,” Transplantation, vol. 59, no. 2, pp. 300–305, 1995. View at: Publisher Site | Google Scholar
  65. V. N. de Paiva, R. M. M. Monteiro, V. de Paiva Marques et al., “Critical involvement of Th1-related cytokines in renal injuries induced by ischemia and reperfusion,” International Immunopharmacology, vol. 9, no. 6, pp. 668–672, 2009. View at: Publisher Site | Google Scholar
  66. M. D. Jose, Y. Ikezumi, N. van Rooijen, R. C. Atkins, and S. J. Chadban, “Macrophages act as effectors of tissue damage in acute renal allograft rejection,” Transplantation, vol. 76, no. 7, pp. 1015–1022, 2003. View at: Publisher Site | Google Scholar
  67. M. Malek and M. Nematbakhsh, “Renal ischemia/reperfusion injury; from pathophysiology to treatment,” Journal of Renal Injury Prevention, vol. 4, no. 2, pp. 20–27, 2015. View at: Publisher Site | Google Scholar
  68. M. Takeiri, M. Tachibana, A. Kaneda et al., “Inhibition of macrophage activation and suppression of graft rejection by DTCM-glutarimide, a novel piperidine derived from the antibiotic 9-methylstreptimidone,” Inflammation Research, vol. 60, no. 9, pp. 879–888, 2011. View at: Publisher Site | Google Scholar
  69. H. R. Jang and H. Rabb, “The innate immune response in ischemic acute kidney injury,” Clinical Immunology, vol. 130, no. 1, pp. 41–50, 2009. View at: Publisher Site | Google Scholar
  70. A. Koenig and O. Thaunat, “Lymphoid neogenesis and tertiary lymphoid organs in transplanted organs,” Frontiers in Immunology, vol. 7, p. 646, 2016. View at: Publisher Site | Google Scholar
  71. S. Stewart, G. L. Winters, M. C. Fishbein et al., “Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection,” The Journal of Heart and Lung Transplantation, vol. 24, no. 11, pp. 1710–1720, 2005. View at: Publisher Site | Google Scholar
  72. P. J. Michaels, J. Kobashigawa, H. Laks et al., “Differential expression of RANTES chemokine, TGF-β, and leukocyte phenotype in acute cellular rejection and quilty B lesions,” The Journal of Heart and Lung Transplantation, vol. 20, no. 4, pp. 407–416, 2001. View at: Publisher Site | Google Scholar
  73. Y. Liu, W. Chen, C. Wu et al., “Macrophage/monocyte-specific deletion of Ras homolog gene family member A (RhoA) downregulates fractalkine receptor and inhibits chronic rejection of mouse cardiac allografts,” The Journal of Heart and Lung Transplantation, vol. 36, no. 3, pp. 340–354, 2017. View at: Publisher Site | Google Scholar
  74. W. Chen, S. Chen, W. Chen, X. C. Li, R. M. Ghobrial, and M. Kloc, “Screening RhoA/ROCK inhibitors for the ability to prevent chronic rejection of mouse cardiac allografts,” Transplant Immunology, vol. 50, pp. 15–25, 2018. View at: Publisher Site | Google Scholar
  75. C. Wu, Y. Zhao, X. Xiao et al., “Graft-infiltrating macrophages adopt an M2 phenotype and are inhibited by purinergic receptor P2X7 antagonist in chronic rejection,” American Journal of Transplantation, vol. 16, no. 9, pp. 2563–2573, 2016. View at: Publisher Site | Google Scholar
  76. W. H. Kitchens, C. M. Chase, S. Uehara et al., “Macrophage depletion suppresses cardiac allograft vasculopathy in mice,” American Journal of Transplantation, vol. 7, no. 12, pp. 2675–2682, 2007. View at: Publisher Site | Google Scholar
  77. Y. Zhao, S. Chen, P. Lan et al., “Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model,” American Journal of Transplantation, vol. 18, no. 3, pp. 604–616, 2018. View at: Publisher Site | Google Scholar
  78. Y. Ikezumi, T. Suzuki, T. Yamada et al., “Alternatively activated macrophages in the pathogenesis of chronic kidney allograft injury,” Pediatric Nephrology, vol. 30, no. 6, pp. 1007–1017, 2015. View at: Publisher Site | Google Scholar
  79. Y. Y. Wang, H. Jiang, J. Pan et al., “Macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury,” Journal of the American Society of Nephrology, vol. 28, no. 7, pp. 2053–2067, 2017. View at: Publisher Site | Google Scholar
  80. D. K. Nayak, F. Zhou, M. Xu et al., “Long-term persistence of donor alveolar macrophages in human lung transplant recipients that influences donor-specific immune responses,” American Journal of Transplantation, vol. 16, no. 8, pp. 2300–2311, 2016. View at: Publisher Site | Google Scholar
  81. D. K. Nayak, F. Zhou, M. Xu et al., “Zbtb7a induction in alveolar macrophages is implicated in anti-HLA–mediated lung allograft rejection,” Science Translational Medicine, vol. 9, no. 398, article eaal1243, 2017. View at: Publisher Site | Google Scholar
  82. J. R. Scalea, Y. Tomita, C. R. Lindholm, and W. Burlingham, “Transplantation tolerance induction: cell therapies and their mechanisms,” Frontiers in Immunology, vol. 7, p. 87, 2016. View at: Publisher Site | Google Scholar
  83. P. Riquelme, S. Tomiuk, A. Kammler et al., “IFN-γ-induced iNOS expression in mouse regulatory macrophages prolongs allograft survival in fully immunocompetent recipients,” Molecular Therapy, vol. 21, no. 2, pp. 409–422, 2013. View at: Publisher Site | Google Scholar
  84. P. Conde, M. Rodriguez, W. van der Touw et al., “DC-SIGN+ macrophages control the induction of transplantation tolerance,” Immunity, vol. 42, no. 6, pp. 1143–1158, 2015. View at: Publisher Site | Google Scholar
  85. P. Riquelme, G. Amodio, C. Macedo et al., “DHRS9 is a stable marker of human regulatory macrophages,” Transplantation, vol. 101, no. 11, pp. 2731–2738, 2017. View at: Publisher Site | Google Scholar
  86. D. A. Hume and K. P. A. MacDonald, “Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling,” Blood, vol. 119, no. 8, pp. 1810–1820, 2012. View at: Publisher Site | Google Scholar
  87. L. A. Robinson, C. Nataraj, D. W. Thomas et al., “A role for fractalkine and its receptor (CX3CR1) in cardiac allograft rejection,” The Journal of Immunology, vol. 165, no. 11, pp. 6067–6072, 2000. View at: Publisher Site | Google Scholar
  88. M. S. Braza, M. M. T. van Leent, M. Lameijer et al., “Inhibiting inflammation with myeloid cell-specific nanobiologics promotes organ transplant acceptance,” Immunity, vol. 49, no. 5, pp. 819–828.e6, 2018. View at: Publisher Site | Google Scholar
  89. F. S. Sutterwala, G. J. Noel, P. Salgame, and D. M. Mosser, “Reversal of proinflammatory responses by ligating the macrophage Fcγ receptor type I,” Journal of Experimental Medicine, vol. 188, no. 1, pp. 217–222, 1998. View at: Publisher Site | Google Scholar
  90. M. S. Braza, P. Conde, M. Garcia et al., “Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance,” American Journal of Transplantation, vol. 18, no. 5, pp. 1247–1255, 2018. View at: Publisher Site | Google Scholar

Copyright © 2019 Junhui Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

1341 Views | 549 Downloads | 6 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at help@hindawi.com to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19. Sign up here as a reviewer to help fast-track new submissions.