Keywords

1 Introduction

Renal fibrosis is a common pathological feature of chronic kidney diseases (CKD) and characterized by excessive extracellular matrix (ECM) deposition and myofibroblast accumulation (Meng et al. 2016a). Macrophages, firstly identified by Metchnikoff over one hundred years ago, are highly diverse and exhibit a wide range of complex roles in host defense, tissue development, homeostasis, tissue injury and repair, and fibrosis (Wilson et al. 2004; Wynn and Vannella 2016). In the kidney, macrophages originate from yolk sac, fetal liver and bone marrow. It is noteworthy that bone marrow myeloid progenitors-derived monocytes are the major source of infiltrated macrophages (Huen and Cantley 2015). In the injured kidney, local production of chemokines induces the infiltration of neutrophils and naïve monocytes from which differentiate into phagocytic macrophages, and then they are polarized and activated in response to the local immune microenvironment (Yona et al. 2013). As the major mediator for inflammatory response, monocytes/macrophages are highly involved in the process of renal injury and repair in many aspects of experimental and human renal diseases (Duffield 2010). They are regarded as a critical link between renal inflammation and fibrosis (Meng et al. 2014). Macrophages, with high heterogeneity and plasticity, are activated and polarized into different phenotypes in the progression of renal disease, they then secrete various cytokines and growth factors accordingly, which may alter the microenvironment in diseased kidney in a feedback loop, the interplay between macrophages and neighboring cells such as immune cells and resident kidney cells may determine the fate of renal diseases (Anders and Ryu 2011; Duffield 2010; Ricardo et al. 2008). In this setting, this chapter highlighted recent progress in the understanding of the role of monocytes/macrophages in renal fibrosis, with a focus on the monocytes/macrophages recruitment, phenotypes, functions, and regulatory mechanisms in progression of renal fibrosis, then the therapeutic potential for macrophage-based or targeted therapy for renal fibrosis were also discussed.

2 Recruitment of Monocytes/Macrophages in the Kidney

Previous studies have shown that the recruitment of bone marrow-derived monocytes into kidney is a critical step for renal inflammation (Braga et al. 2018), with extensive discussion on the several key chemokines involved. CCR2 and its main ligand, CCL2 (also called MCP-1), are indicated in various types of kidney diseases; they are responsible for the recruitment of Ly6CHigh monocytes and regulation of bone marrow-derived fibroblasts in injured kidney (Braga et al. 2018). Emerging evidence further shows that knockout of CCR2 and 4, instead of CCR3 and 5, attenuates renal fibrosis (Braga et al. 2018), these results are further confirmed by the finding that treatment of CCX140-B, a CCR2 inhibitor, protects against type 2 diabetic nephropathy (Weir 2015). Transforming growth factor-β (TGF-β) is reported to up-regulate the expression of CCL2 in macrophages and then promote monocyte recruitment and macrophage accumulation (Border and Noble 1994). The interaction between CX3CL1 and CX3CR1 is also responsible for the infiltration of Ly6C-CX3CR1high macrophages, which contribute significantly to unilateral ureteral obstruction (UUO)-induced renal fibrosis (Peng et al. 2015). Additionally, chemokine CXCL16 and its receptor CXCR6 play important roles in recruiting monocytes from circulation to the injured kidney in UUO nephropathy, hypertensive nephropathy, and ischemia-reperfusion acute kidney injury (AKI) (Chen et al. 2011; Xia et al. 2013, 2014a, b). Tubular-derived IL-34, being one of the macrophage differentiation and growth factors, shares a common receptor with macrophage colony-stimulating factor (M-CSF). It fails to alter kidney macrophages’ activation phenotypes but induces persistent tubular injury via macrophage recruitment and proliferation in the later stages of tubular repair and fibrosis (Baek et al. 2015). Newer evidence shows that the accumulation of B cells in the early stage of kidney injury enhances monocyte/macrophage mobilization and recruitment, thereby accelerates renal fibrosis in UUO nephropathy (Han et al. 2017).

3 Activation and Polarization of Monocytes/Macrophages in the Kidney

As aforementioned, bone marrow myeloid progenitors-derived monocytes are the major source for infiltrated macrophages (Duffield 2010; Wilson et al. 2004). Monocytes could be categorized into different subsets as defined by lymphocyte antigen 6C (Ly6C), an antigen representing the stages of a continuous maturation pathway, and chemokine receptor profiles like CCR2 and CX3CR1 (Ricardo et al. 2008; Sunderkötter et al. 2004). For example, CCR2+Ly6C+ monocyte recruited to the site of inflammation has been identified as a specific monocyte subset that functions in immune response and tissue remodeling (Geissmann et al. 2003). Monocytes then differentiate into macrophages with distinct activation states in response to local microenvironment. To represent the Th1/Th2 paradigm, classification of M1/M2 macrophages has been widely used, although it may be a gross oversimplification of representing the expanded phenotype diversity accurately (Guilliams et al. 2014; Martinez and Gordon 2014; Murray et al. 2014; Wermuth and Jimenez 2015). Pro-inflammatory M1 macrophages, also termed as classically activated macrophages, are induced by interferon (IFN)-γ and lipopolysaccharide (LPS) in vitro, while wound healing/pro-fibrotic M2 macrophages, also called alternatively activated macrophages, are generated by interleukin (IL)-4 and IL-13 incubation. M2 macrophages could be further subcategorized based on different stimuli and functions: IL-4 and IL-13 trigger M2a macrophages; immune complexes induce M2b macrophages; IL-10 plus TGF-β or glucocorticoids induce anti-inflammatory M2c macrophages (Anders and Ryu 2011). In the injured kidney, macrophages are activated by multiple factors, which include other types of immune cells like T cells and NK cells, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and immune complexes (Anders 2010; Duffield 2010). M1 macrophages are generally induced by pro-inflammatory cytokines like IFN-γ, LPS, and TNF-α while M2 macrophages are polarized by Th2 cytokines, and macrophages gained M2 phenotype after engulfing apoptotic cells (Anders and Ryu 2011; Swaminathan and Griffin 2008; Vinuesa et al. 2008). Evidence shows that high level of iNOS, instead of Arginase 1, is expressed in macrophages 24 h post-injury, indicating that pro-inflammatory M1 macrophages become predominant in the early stage of kidney diseases (Lee et al. 2011). Additionally, polarization between M1 and M2 is also detectable in vivo, which is supported by the finding that IFN-γ-stimulated M1 cells can switch to M2 in the repaired kidney after being injected in the early stage of AKI model (Lee et al. 2011).

Macrophages derived from circulating inflammatory Ly6Chigh monocytes could also be divided into three subcategories depending on the level of Ly6C markers (Clements et al. 2016; Lin et al. 2009). CD11b+/Ly6Chigh macrophages are associated with the initiation of renal injury, they mimic the function of M1 macrophages by producing abundant pro-inflammatory cytokines (e.g., TNF-α) and chemokines (e.g., MIP-1) (Meng et al. 2015). Deletion of circulating monocytes and recruited Ly6Chigh macrophages attenuates renal fibrosis (Lin et al. 2009). The number of the CD11b+/Ly6Cintermediate macrophages is significantly increased during the repair stage. By contrast, CD11b+/Ly6Clow macrophages are predominant in renal fibrosis through producing pro-fibrotic factors including platelet-derived growth factor (PDGF), insulin-like growth factor (IGF)-1, and CCL17, which are highly correlated to wound healing and fibrogensis (Duffield 2010). Additionally, gene signature in CD11b+/Ly6Clow macrophages has been well defined and within the significantly altered genes, SPARC regulates the production of ECM while TIMP2 prevents MMPs-mediated ECM turnover and enhances matrix accumulation (Fan et al. 2014; Wang et al. 2010). Additionally, Macrophages-derived IGF-1 attenuates myofibroblast apoptosis and enhances collagen production (Wynes et al. 2004). In rhabdomyolysis-induced AKI mouse model, macrophage polarization was detected during the disease progression, an abundance of F4/80lowCD11bhighLy6bhighCD206low macrophages was found in kidney two days after rhabdomyolysis, whereas F4/80highCD11b+Ly6blowCD206high cells became predominant by day 8 (Belliere et al. 2015). All these evidences indicate the pro-fibrotic role of CD11b+/Ly6Clow macrophages in renal fibrosis.

4 Role of Monocytes/Macrophages in Kidney Injury

Glomerular and interstitial macrophage infiltration is detectable in different types of AKI and progressive CKD of both experimental models and human biopsies (Wilson et al. 2004). Classically activated macrophages produce pro-inflammatory factors like IL-1, TNF-α, IL-6, IL-23, ROS, NO, and iNOS, overproduction of these factors induces severe kidney damage. Pro-inflammatory macrophages infiltration is highly correlated with the degree of renal damage in both AKI and CKD models. By using different macrophage depletion and transfer techniques, pathogenic roles of these pro-inflammatory macrophages have been determined in different kidney disease models (Cao et al. 2013). Liposomal clodronate-mediated macrophage depletion in early stage of ischemia-reperfusion injury (IRI) and rhabdomyolysis-induced AKI significantly reduces renal injury and long-term renal fibrosis, indicating the pathogenic role of M1 macrophages in the initiation of kidney injury (Belliere et al. 2015; Day et al. 2005; Jo et al. 2006; Ko et al. 2008). Additionally, depletion of macrophages with clodronate liposome or CCR2 deficiency attenuates renal injury and fibrosis in UUO nephropathy (Kitagawa et al. 2004; Kitamoto et al. 2009). Pro-inflammatory macrophages also mediate renal injury in CKD model, macrophages deletion or deactivation by clodronate, c-fms inhibitor, or JNK inhibitor prevents the progression of crescentic anti-GBM glomerulonephritis (D’Souza et al. 1999; Han et al. 2011; Ma et al. 2009). In contrast, adoptive transfer of bone marrow-derived macrophages in early stage of the same disease model enhances renal injury (Ikezumi et al. 2003). Taken together, pro-inflammatory M1 macrophages enhance renal injury possibly through mechanism as follows: First, accelerating renal inflammation by releasing an abundance of pro-inflammatory cytokines and chemokines (Cao et al. 2013); second, overproduction of ROS and TNF-α by macrophages induces apoptosis of renal resident cells, including tubular epithelial cells (TECs) and endothelial cells, and prevents their proliferation, thereby increases renal injury (Kluth et al. 2004); third, a plethora of pro-fibrotic cytokines and growth factors released from macrophages triggers abnormal wound healing and leads to renal fibrosis eventually (Anders and Ryu 2011).

5 Role of Monocytes/Macrophages in Kidney Repair

Anti-inflammatory and reparative roles of macrophages have been well studied (Day et al. 2005; Huen and Cantley 2015; Lee et al. 2011). M2 macrophages and CD11b+/Ly6Cintermediate macrophages become predominant in the repair stage of kidney disease models such as IRI and UUO nephropathy, and they serve as key regulators for renal inflammation resolution and wound healing (Cochrane et al. 2005; Lee et al. 2011). Fluorescence-labeled cell tracing study shows that 6 days after IRI, a majority of macrophages loss iNOS markers and gained high level of Arginase 1, showing the phenotypic switch of macrophages toward M2 in the repair phase of AKI (Lee et al. 2011). Depletion of macrophages in late stage of IRI model reduces TEC proliferation and delays renal repair, but transferring IL-4-polarized M2 macrophages induces the repair process (Vinuesa et al. 2008). IL-4/IL-13-polarized M2a macrophages are essential for the recovery from ischemic AKI (Zhang et al. 2017). Additionally, calcium-binding protein S100A8/A9 complex, as a typical DAMP, promotes M2 polarization, thereby increases renal repair following IRI (Dessing et al. 2015). M2 macrophages exhibit anti-inflammatory effect mainly through induction of anti-inflammatory factors and high endocytic capacities (Ricardo et al. 2008). M2 macrophages synthesize an abundance of IL-10 after engulfing unwanted cells and their debris. They produce other anti-inflammatory cytokines and trophic factors like TGF-β, IGF, and hepatocyte growth factor (HGF). M2 macrophages can deactivate T cells and macrophages to alleviate renal inflammation. It is noteworthy that M2c macrophages induce production of Tregs to exert more powerful anti-immunological effects compared with other subtypes (Lu et al. 2013; Mu et al. 2005). Moreover, M2 macrophages stimulate angiogenesis and promote endothelial repair (Mantovani et al. 2013). Failure of polarization from pro-inflammatory M1 to reparative M2 macrophages leads to progressive renal inflammation and fibrosis after IRI (Lech et al. 2014). Macrophage-derived Wnt7b signaling enhances epithelial response and accelerates renewal of stem cells or progenitor cells, thereby induces renal repair following IRI directly (Lin et al. 2010). BRP-39, a macrophage-produced chitinase-like protein, prevents tubular apoptosis in a PI3K/AKT-dependent manner (Schmidt et al. 2013). Macrophage-derived HO-1 also contributes to macrophage-mediated renoprotective effect (Ferenbach et al. 2010, 2011). Furthermore, cross talk between injured tubular cells and activated macrophages via retinoic acid signaling also coordinates tubular repair (Chiba et al. 2016).

6 Role of Monocytes/Macrophages in Kidney Fibrosis and Fibrolysis

Anti-inflammatory macrophages promote tubular re-epithelialization via the production of trophic factors. However, unresolved or severe inflammation initiates renal fibrosis (Anders and Ryu 2011). Evidence shows that depletion of macrophage attenuates renal fibrosis in most occasions, showing the pro-fibrotic effect of macrophages in various renal diseases (Meng et al. 2014; Vernon et al. 2010; Zeisberg and Duffield 2010). For example, depletion of monocytes/macrophages by liposome-encapsulated clodronate (LEC) lowers blood pressure and reduces hypertensive renal injury and fibrosis (Huang et al. 2018). Liposomal clodronate-mediated depletion of macrophages prevents renal fibrosis following IRI and UUO nephropathy (Ko et al. 2008; Sung et al. 2007), this is further evidenced by the finding that mutation of MCP-1 gene significantly suppresses renal fibrosis (Wada et al. 2004). Of note, large numbers of M2 macrophages, detected in the active fibrotic area in renal biopsy of IgA patients, are positively correlated with the severity of glomerulosclerosis and interstitial fibrosis (Ikezumi et al. 2011). Consistently, glucocorticoid treatment accelerates global glomerulosclerosis in rat thy-1 mesangial proliferative glomerulonephritis, and it is correlated with increased numbers of M2 macrophages (Ikezumi et al. 2010). Moreover, deficiency of macrophages in fibrotic phase prevents renal fibrosis via reducing TGF-β1 expression and capillary rarefaction (Han et al. 2013). Collectively, macrophages promote renal fibrosis possibly through mechanisms as followed: First, M2 macrophages produce numbers of pro-fibrotic factors, such as TGF-β1, fibroblast growth factor 2 (FGF-2), PDGF, and galectin-3, which promote myofibroblast proliferation, survival, and activation, and overproduction of ECM (Floege et al. 2008; Henderson et al. 2008; Wynes et al. 2004), although macrophage-derived TGF-β1 may not be essential for UUO-induced renal interstitial fibrosis (Huen et al. 2013); second, macrophage-derived cytokines and factors, such as IL-1, matrix metalloproteinases (MMP)-9, TGF-β1, angiotensin (Ang)-II, PDGF, IGF-1 and FGF-2, enhance myofibroblasts transdifferentiation or activation from tubular epithelial cells via epithelial-mesenchymal transition (EMT), endothelial cells via endothelial-mesenchymal transition (EndoMT), pericytes, local fibroblasts, and mesangial cells (Falke et al. 2015; LeBleu et al. 2013; Meng et al. 2013). Third, macrophages produce fibronectin and collagen in response to pro-fibrotic microenvironment (Gratchev et al. 2001; Schnoor et al. 2008). Emerging evidence indicates that monocytes/macrophages transdifferentiate into collagen-producing fibrocytes (Duffield 2010) or directly into myofibroblast-like cells (Bertrand et al. 1992; Chen et al. 2014; Mooney et al. 2010; Nikolic-Paterson et al. 2014; Pilling and Gomer 2012). Fourth, activated macrophages damage glomerular and peritubular capillaries, and thereby promote hypoxia-driven fibrosis (Fine and Norman 2008; Han et al. 2013). However, we should note that M2 macrophages might not definitely contribute to renal fibrosis (Anders and Ryu 2011). Inflammation and epithelial healing characterize the first-line danger response program for wound healing. Fibrosis, a major event in the second-line danger response program, only occurs when epithelial healing is incomplete or insufficient, such as in the cases of sustained injury and unresolved renal inflammation (Gurtner et al. 2008). During inflammatory response, bone marrow-derived macrophages are recruited into the inflamed kidney and further differentiate into collagen-producing myofibroblasts locally in the injured kidney via newly identified phenomenon termed macrophage-to-myofibroblast (MMT) (Wang et al. 2016, 2017; Meng et al. 2016b; Tang et al. 2018). The MMT cells can be recognized by their co-expression of macrophage (CD68) and myofibroblast (α-smooth muscle actin, α-SMA) markers in the diseased kidney and account for more than half of α-SMA-expressing macrophages in both human and experimental models of chronic kidney diseases including chronic renal allograph rejection (Wang et al. 2016, 2017; Meng et al. 2016b; Tang et al. 2018). However, some studies show that bone marrow-derived cells make only a small fraction of contribution to myofibroblasts directly; these conflicting results warrant further investigation (Lin et al. 2008; Roufosse et al. 2006; Kramann et al. 2018).

In the fibrolysis stage, macrophages could serve as a negative regulator for renal fibrosis (Anders and Ryu 2011). Evidence shows that fibrolytic macrophage promotes resolution of renal fibrosis through producing matrix metalloproteinases (MMPs), and thereby degrades ECM in fibrotic kidney (Anders and Ryu 2011; Ronco and Chatziantoniou 2008). However, the exact phenotype for fibrolytic macrophage is not fully understood. Regression of established fibrosis has been well studied in liver, depletion of macrophages in the late stage of CCL4-induced liver fibrosis prevents the clearance of liver scars, which may be caused by the loss of macrophage-triggered hepatic stellate cell (HSC) apoptosis (Duffield et al. 2005a), Moreover, macrophage-produced MMP-13 removes fibrotic scar in liver (Fallowfield et al. 2007). Transfer of bone marrow-derived macrophages reverses liver fibrosis and promotes liver recovery (Thomas et al. 2011). In kidney, deficiency of angiotensin II type 1 receptor (AngIIr1) reduces the phagocytic activity of macrophages, thereby promotes renal fibrosis as compared with mice transplanted with AngIIr1+/+ bone marrow cells in the late phase of UUO nephropathy (Nishida et al. 2002). Additionally, urokinase-type plasminogen activator receptor (uPAR) enhances macrophage infiltration and scavenger receptor function, therefore increasing the resolution of renal fibrosis (Zhang et al. 2003). In addition, adoptive transfer of macrophages 14 days after UUO surgery attenuates renal fibrosis and enhances renal repair in a MMP-2-dependent manner (Nishida et al. 2005, 2007). Of note, functions of MMPs vary in different stages of renal diseases, for example, MMP-2 and MMP-9 are pathogenic by destroying glomerular and tubular basement membranes and inducing EMT in early stage of renal diseases (Cheng and Lovett 2003; Cheng et al. 2006; Rao et al. 2006; Ronco et al. 2007).

7 Regulatory Mechanisms of Macrophage Polarization in Renal Fibrosis

Molecular mechanisms underlying the activation and polarization of macrophages have been extensively investigated (Meng et al. 2015). Increasing evidence shows that macrophage polarization is regulated by various transcriptional factors like STATs, PPARs, KLFs, and C/EBP and multiple signaling pathways such as NF-κB, JNK, JAK/STAT, PI3K/AKT, Wnt/β-catenin, and Notch signals (Kapoor et al. 2015; Piccolo et al. 2017; Zhou et al. 2014). Some other mediators have also been identified, for example, high-mobility group box 1 (HMGB1) protein produced by TEC and infiltrated macrophages contribute to the M1 macrophage activation, as shown by the high level of iNOS and suppression of IL-10 in macrophages. Blocking HMGB1 production with a glycyrrhizic acid derivative reduced M1 polarization, kidney injury and fibrosis in UUO nephropathy (Tian et al. 2015). Knockout of suppressor of cytokine signaling-3 (SOCS-3), a critical intracellular negative regulator, enhances cell proliferation and M2 activation in a JAK/STAT-dependent mechanism while overexpression of SOCS-3 in TECs induces classical activation of the cocultured macrophages, indicating its role in macrophage polarization (Susnik et al. 2014). A recent study showed that myeloid-specific knockout of the transcription factor recombination signal binding protein-Jκ (RBP-J), a modulator essential for Notch activation, decreased monocyte infiltration and macrophage activation, thereby alleviated renal fibrosis (Jiang et al. 2018).

Mediators for M2 polarization have also been extensively reviewed. CSF-1 is an important inducer for macrophage polarization. Loss of CSF-1 reduces M2 macrophages, thereby inhibits TEC proliferation and tubular repair (Menke et al. 2009; Zhang et al. 2012). This is confirmed by the finding that CSF-1 promoted renal crystals clearance in hyperoxaluric mice via increasing the number of CD11b+F4/80+CD163+CD206high M2 cells (Taguchi et al. 2014). Although granulocyte-macrophage (GM)-CSF usually induces the differentiation of peripheral Ly6Chigh monocytes to pro-inflammatory M1 macrophages (Lenzo et al. 2012; Murray and Wynn 2011), a recent in vivo study identified macrophages with a unique alternative activation state in response to GM-CSF, they were found in macrophages isolated from repair phase of injured kidneys in IRI model and promoted tubular proliferation and repair (Huen et al. 2015; Takeda et al. 1996). Additionally, treatment of IL-25, a novel cytokine for M2 polarization both in vivo and in vitro, prevents renal injury in adriamycin nephropathy via a IL-4/IL-13-dependent manner (Cao et al. 2011). Netrin-1 is an anti-inflammatory molecule induced in TECs from IRI model; it suppresses monocyte migration and function by targeting chemokines and NF-κB signaling. Netrin-1 transgenic mice show an increase in M2 macrophages infiltration with upregulation of IL-4, IL-13, and arginase-1 in a PPAR-dependent mechanism, showing that Netrin-1 is a critical inducer for M2 polarization (Ranganathan et al. 2013). Calcitriol, a bioactive 1,25-dihydroxyvitamin D3, promotes M2 polarization while inhibiting macrophage recruitment and activation, thereby attenuates proteinuria and renal injury in diabetic nephropathy (Zhang et al. 2014). In addition, loss of p53 from bone marrow accelerates renal injury and impairs renal repair caused by the deficiency of KLF4 expression and M2 polarization (Sutton et al. 2013). Moreover, paracrine effects of mesenchymal stem cells (MSCs) increases the infiltration of M2 macrophages which protects against renal acute injury, and the adoptive transfer of MSCs-cocultured macrophages in macrophage depletion mice induces much milder renal injury compared with control (Geng et al. 2014). The functions of MSCs on M2 polarization have also been reported in IRI injury (Wise et al. 2014). Additionally, recent in vivo studies showed that Wnt/β-catenin signaling promoted renal fibrosis by enhancing macrophage proliferation and M2 polarization in STAT3-dependent mechanisms (Feng et al. 2018a, b).

8 Monocyte/Macrophage-Based or Targeted Therapy in Treatment of Renal Fibrosis

Till now, therapeutic strategies by interfering with monocyte/macrophage recruitment, activation and polarization, or adoptive transfer of polarized macrophages have been extensively studied.

Previous studies showed that DNA vaccination or neutralized antibody-mediated inhibition of chemokines, like CCL2 and CCL5, prevents macrophage infiltration and renal damage in adriamycin nephropathy (Wu et al. 2005; Zheng et al. 2006), nephrotoxic serum nephritis (Lloyd et al. 1997; Tang et al. 1996; Wada et al. 1996), and anti-thy1.1 nephritis (Wenzel et al. 1997). Inhibition of CX3CR1 or intercellular adhesion molecule-1 (ICAM-1) protects against crescentic glomerulonephritis and nephrotoxic nephritis (Feng et al. 1999; Kawasaki et al. 1993). Additionally, anti-macrophage serum-induced depletion of macrophage prevents experimental glomerulonephritis (Holdsworth et al. 1981). Blocking c-fms, a receptor for CSF, protects against UUO and diabetic nephropathy by reducing the recruitment and proliferation of macrophages (Le Meur et al. 2002; Lim et al. 2009). Moreover, liposomal clodronate-mediated clearance of macrophage alleviates renal fibrosis (Kitamoto et al. 2009), this finding is further confirmed by the study showing that conditional depletion of CD11b+ cells attenuates crescentic glomerulonephritis (Duffield et al. 2005b; Wang and Harris 2011). Notwithstanding, inconsistent evidence shows that blocking CCL2 or CCL5 fails to attenuate renal injury, indicating that the success of therapy by inhibiting macrophages recruitment might depend on the types and stages of kidney diseases (Anders et al. 2003; Clauss et al. 2009).

Accumulating evidence shows that modification of macrophage activation states could also prevent renal fibrosis. A recent study demonstrated that Beta-2 adrenergic receptor (β2AR) agonists increased the binding of β-arrestin2 and IκBα, leading to the down-regulation of NF-κB and deactivation of macrophages, thereby protected against diabetic renal complication (Noh et al. 2017). Blocking NF-κB signaling by antisense oligonucleotides or its natural inhibitor IκB suppresses the classical activation of macrophages but increases anti-inflammatory macrophages, thereby limits kidney injury (Tomita et al. 2000; Wilson et al. 2005). By increasing IL-4/IL-13-mediated M2 polarization, IL-25 protects against adriamycin nephropathy (Cao et al. 2011). Additionally, treatment of Quercetin reduced macrophage infiltration and M2 polarization by preventing ECM production and interstitial fibrosis in a TGF-β1/Smad-dependent mechanism in obstructive nephropathy (Lu et al. 2018).

Modified macrophages are directly used to treat renal diseases in some studies. IL-4/IL-13-polarized M2a spleen macrophages were transferred into SCID mice where functions of endogenous immune cells were excluded, results showed that renal histology and function were both restored in adriamycin nephropathy (Wang et al. 2007). The protective effect of ex vivo polarized macrophages was further confirmed in streptozotocin-induced type 1 diabetic nephropathy (Parsa et al. 2012). Of note, IL-10 and TGF-β-induced M2c macrophages show high efficiency in reducing renal damage and proteinuria compared with M2a, because they are capable of inducing immunosuppressing regulatory T cells differentiation via a B7-H4-dependant mechanism (Cao et al. 2010; Lu et al. 2013). IL-10/TGF-β or IL-4/IL-13-modified bone marrow-derived macrophages have limited protective effect due to the finite proliferation capacity of bone marrow cells, so it may confine the clinical application of macrophage-based therapy by modifying bone marrow cells from patients (Cao et al. 2014).

9 Conclusions and Perspective

Taken together, monocytes and macrophages are recruited into the injured kidney by chemokines released from kidney, and then they are activated and polarized into distinct phenotypes in response to the local microenvironment. Macrophages with different activation stages exert distinct or even diverse effects in the processes of renal injury, repair, and fibrosis (Fig. 13.1). Uncontrolled M2 macrophages or CD11b+/Ly6Clow macrophages promote renal fibrosis via paracrine effects or direct transition to myofibroblast-like cells. In this regard, inhibiting monocyte/macrophage recruitment, modifying macrophage activation and polarization, or adoptive transfer of polarized macrophages may be promising therapies for renal fibrosis.

Fig. 13.1
figure 1

Polarization and function of macrophages in renal injury, repair, and fibrosis

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