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Chemokines in Renal Injury

Arthur C. K. Chung and Hui Y. Lan

Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China

ABSTRACT The main function of is to guide inflammatory cells in their migration CXCR1 and CXCR2 receptors (Figure 2). In- to sites of . During the last 2 decades, an expanding number of flammatory cells such as T-helper1 (Th1) chemokines and their receptors have driven broad inquiry into how inflammatory cells and natural killer cells are at- cells are recruited in a variety of diseases. Although this review focuses on chemo- tracted by chemokines binding to kines and their receptors in renal injury, proinflammatory IL-17, TGF␤, and TWEAK CXCR3, CXCR6, CCR5, and CX3CR1 signaling pathways also play a critical role in their expression. Recent studies in to induce local type 1 (IL-2, INF- transgenic mice as well as blockade of signaling by neutralizing ligands ␥)–mediated inflammatory responses, or receptor antagonists now allow direct interrogation of chemokine action. The whereas Th2 cells and are re- emerging role of regulatory T cells and Th17 cells during renal injury also forges cruited by ligands for CCR3, CCR4, and tight relationships between chemokines and infiltration in the development CCR8 during a type 2 cytokine (IL-4, IL-5, of kidney disease. As blockade inches toward clinical use, the and IL-13)-mediated inflammatory re- field remains an attractive area with potential for unexpected opportunity in the sponses. CCR6 and CXCR3 receptors are future. detected on Th17 cells and a spectrum of chemokines receptors are expressed in reg- J Am Soc Nephrol 22: 802–809, 2011. doi: 10.1681/ASN.2010050510 ulatory T cells (Tregs), such as CCR4–8, CXCR3, and CXCR6. In kidneys, endothe- lial cells, podocytes, mesangial cells (MCs), Renal inflammation underlies many 1).6,7 The large CC chemokine family has tubular epithelial cells, and interstitial fi- chronic kidney diseases and the infiltra- the first two cysteine residues adjacent to broblasts can also produce inflammatory tion of leukocytes mediates much of the each other, whereas the CXC family has a chemokines upon stimulation.3,9 nephritogenic inflammatory response. single residue in between the As several recent reviews have dealt with first two cysteines. Fractalkine (CX3CL1) is the basic biology, mouse models, and the only member of the CX3C chemokine REGULATION OF CHEMOKINE blockade studies of chemokines in renal family where three amino acid residues EXPRESSION diseases,1–11 we focus here on recent de- separate the first two cysteines. Finally, two velopments in pathophysiology of that related chemokines absent the two cysteine On the basis of their regulation and pro- chemokine effect. residues that bind the XCR1 receptor be- duction, chemokines can be classified long to the XC family. As shown in Figure broadly as homeostatic/lymphoid or in- 1, many chemokines bind multiple recep- flammatory chemokines. The former is CHEMOKINES AND CHEMOKINE tors and most receptors bind multiple responsible for leukocyte homing and RECEPTORS chemokines. However, CC chemokine re- ceptors exclusively bind CC chemokines Published online ahead of print. Publication date Chemokines are a group of chemotac- and CXC receptors bind only CXC chemo- available at www.jasn.org. tic (approximately 8 to 17 kines. Correspondence: Dr. Hui Y. Lan, Department of kD) with the ability to bind G-– Chemokines and their corresponding Medicine and Therapeutics, Li Ka Shing Institute of coupled receptors and act as potent at- receptors are expressed in different cell Health Sciences, The Chinese University of Hong tractants for leukocytes in acute and types (Figure 2).7,12 Generally speaking, Kong, Prince of Wales Hospital, Shatin, The New Territories, Hong Kong, China. Phone: 852-3763 chronic inflammation. There are four are mostly attracted by CCL 6077; Fax: 852-2145 7190; E-mail: hylan@cuhk. subfamilies of chemokines, including chemokines acting through CCR1, CCR2, edu.hk 7,6 CCL, CXCL, CX3CL, and CL (Figure 1). andCCR5receptors,whereasneutrophilsare Copyright © 2011 by the American Society of At present, 19 receptors are known (Figure the target of CXCL chemokines through Nephrology

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1. CC subfamily 2. CXC subfamily sure, or acute inflammation.3 Proinflamma- ␣ ␤ Chemokines Receptors Chemokines Receptors tory cytokines, such as TNF- and IL-1 , I-309/CCL1 CCR8 IL-8/CXCL8 CXCR1/2 and reactive oxygen species are major MCP-1/CCL2 CCR2/4/10 GCP-2/CXCL6 CXCR1/2 mediators responsible for chemokine MCP-2/CCL8 CCR2 NAP-2/CXCL7 CXCR2 expression3,7 through the NF-␬B path- MCP-3/CCL7 CCR1/2 ENA-78/CXCL5 CXCR2 α way,13 including connective tissue MCP-4/CCL13 CCR1/2 GRO /CXCL1 CXCR2 β 14 MIP-1α/CCL3 CCR1/5 GRO /CXCL2 CXCR2 -stimulated NF-␬B. In- GROγ/CXCL3 CXCR2 MIP-1β/CCL4 CCR5 PF4/CXCL4 Unknown flammatory chemokines are also in- MIP-3α/CCL20 CCR6 IP-10/CXCL10 CXCR3 duced by other mediators, including RANTES/CCL5 CCR1/3/5 Mig/CXCL9 CXCR3 cyclic adenosine monophosphate, eotaxin-1/CCL11 CCR3 I-TAC/CXCL11 CXCR3 eotaxin-2/CCL24 CCR3 SDF-1α/β/CXCL12 CXCR4 growth factors such as PDGF, basic fi- eotaxin-3/CCL26 CCR3 BCA-1/CXCL13 CXCR5 broblast growth factors, pathogen- HCC-1/CCL14 CCR1 CXCL16 CXCR6 HCC-2/CCL15 CCR1/3 BRAK/CXCL14 Unknown associated molecules such as lipopoly- HCC-4/CCL16 CCR1/3 saccharides, Ig aggregates, LDL, IFN-␥, TARC/CCR17 CCR4 3. XC subfamily and vasoactive substances like angio- MDC/CCL22 CCR4 tensin II, or under diabetic condi- ELC/CCL19 CCR7 Chemokines Receptors 7,15 ␤ SLC/CCL21 CCR7 Lymphotactin/XCL1 XCR1 tions. Activation of TGF /Smad2,3 TECK/CCL25 CCR9 SCM-1b/XCL2 XCR1 signaling during renal inflammation CTACK/CCL27 CCR10 also produces a chemotatic effect on MEC/CCL28 CCR10 4. CX subfamily PARC/CCL16 Unknown by inducing MPIF-1/CCL23 Unknown Chemokines Receptors chemoattractant protein-1 (MCP-1)/ vMIP-II Multiple Fractalkine/CXCL1 CX3CR1 CCL2 expression.16,17 Furthermore, urinary levels of TWEAK, a Figure 1. Chemokines and their receptors. Four subfamilies of chemokines have been cytokine of the TNF superfamily, signifi- characterized, including the CC subfamily, the CXC subfamily, the XC subfamily, and the cantly increase and correlate with the activity CX subfamily. of renal disease in patients with active lupus nephritis.18 Exposure to TWEAK also in- IL-1β, TNF-α, ROS, LPS, IL-17, IL-23, IFN-γ, TGF-β... duces MCP-1/CCL2, RANTES/CCL5, MIP- 1␣/CXCL2, intraperitoneally-10/CXCL10, and SLC/CCL21 in MCs or tubular epithelial ␬ CXCL1–3/5–8CCL2–5/8/13–16 CXCL4/9–11/16 CCL17/19/21/22 cells through a noncanonical NF- B path- CX3CL1 CCL1–5/7/8/11/12 way, thereby promoting leukocyte recruit- CCL14–17/19/21–27 ment to the kidney during injury.19,18,20 The IL-17/IL-23 signaling pathway through Th17 cells also regulates the produc- CCR1/2/5/8 CXCR3/6 CXCR1/2CXCR1/2 CX3CR1 CCR2–10 CCR4/6–8 tion of Th1-attracting chemokines and in- flammatory cell infiltration. In mouse MCs, IL-17 enhances the production of MCP-1/ CCL2, MIP-1␣/CCL3, LARC/CCL20, and NeutrophilsNeutrot phphils Monocytes T cells Dendritic cells MIP-2/CXCL2 through the MAPK path- ways (p38 MAPK and ERK1/2) to recruit T cells and monocytes.21–23 Mice infused with AKI CKD Th17 cells also develop albuminuria, which is associated with higher levels of renal GRO-␣/ Figure 2. Interaction of chemokines and receptors on leukocyte subsets during acute CXCL1 and in glomeruli.24 and chronic kidney injury. Kidney diseases are characterized by the accumulation of various leukocyte subsets that are controlled by chemokines through their corresponding receptors expressed by the different subsets. Although infiltration of neutrophils and ROLE OF CHEMOKINES IN ACUTE monocytes mediate acute kidney injury, activation of T cells, macrophages, and dendritic KIDNEY INJURY cells promote progression of chronic kidney disease. Rapid accumulation of neutrophils and recirculation under normal In the normal kidney, production of in- monocyte/macrophages in injured kidney is conditions, whereas the inflammatory flammatory chemokines is low, but is signif- an essential feature of the innate immune re- chemokines contribute to progression of icantly increased under pathophysiological sponse induced by ischemia-reperfusion in- inflammatory diseases.7 circumstances such as ischemia, toxin expo- jury (IRI).25 Several chemokine families

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show a strong relationship to acute kidney in- Recent studies also reveal a role for Several recent reports highlight the jury (AKI), including the CXCL subfamily— CXCR3 in IRI in mice. CXCR3 is mainly protective role of Tregs during IRI.40–43 IL-8/CXCL8, Gro-␣/CXCL1, and MIP-2/ expressed on activated Th1 cells to medi- However, the source of the renal Tregs in Gro-␤/CXCL2—that act primarily on ate Th1 recruitment.32 CXCR3 ligands response to IRI is uncertain. As renal ex- neutrophils (Figure 2), the CCL subfamily (intraperitoneally-10/CXCL10 and Mig/ pression of MCP-1/CCL-2 is greatly ele- (MCP-1/CCL2), the CX3CL subfamily CXCL9) are upregulated in postischemic vated after IRI and CCR2 has been (fractalkine/CX3CL1) that have specific ef- tissue and CXCR3-deficient kidneys with shown to guide Tregs toward arthritic fects on monocytes and monocyte-derived IRI decrease their infiltration of IFN-␥– joints, CCL chemokines may function to lineages, and RANTES/CCL5 that operate producing CD4ϩ T cells as well as the regulate Treg cell accumulation in acute more broadly to attract cells monocytes and severity of acute tubular necrosis.33 This kidney injury.44,36,45 (Figure 2).10 protective effect is abrogated by adoptive Dendritic cells (DCs) are also an impor- transfer of wild type CD3ϩ cells into tant link between innate and adaptive im- Role of the CXCL Family in Innate CXCR3 null mice,33 demonstrating a munity and their role in renal injury is well Immune Responses in AKI critical role for CXCR3 in Th1 cell re- known.46 After IRI, renal DCs produce both After IRI, an increase in the expression of cruitment to the ischemic kidney. Fur- the proinflammatory cytokines (TNF-␣, IL-8/CXCL8 and Gro-␣/CXCL1 associ- thermore, administration of IL-13, a potent IL-6, and CCL) and chemokines (MCP-1/ ates with marked infiltra- Th2 cytokine, also exhibits an inhibitory ef- CCL2 and RANTES/CCL5).47 Thus, secre- tion,26,27 suggesting that CXCL chemo- fect on interstitial infiltration by neutrophils tion of these CCL chemokines from DCs kines play a significant role in neutrophil and macrophages, which associates with re- may attract monocyte/ to the recruitment. The ability of IL-8/CXCL8 duced expression of MIP-2/Gro-␤/CXCL2, site of inflammation. to recruit neutrophils by upregulating IL-8/CXCL8, and MCP-1/CCL2,34 support- Increased fractalkine/CX3CL1 ex- tubular ICAM-1, by engaging their cog- ing the involvement of CXCL chemokines in pression in injured endothelial cells and nate receptor, CXCR-1, to activate the the T cell infiltration of AKI. blood vessels is also observed in AKI.48,49 p38 MAPK signaling pathway reveals an CX3CR1 is predominantly expressed on essential role of the CXCL family in the Role of CCL and CXC3L Families in macrophages and blockade of CX3CR1 process of neutrophil recruitment.28 AKI by neutralizing antibody or inac- The functional role of CXCL family in Presently, it is known that macrophages in tivation protects the kidney from isch- AKI is clearly demonstrated by finding that the inflamed kidney are either recruited emic injury by inhibiting macrophage treatment with a CXCR2 inhibitor or neu- from the circulation or derived from the infiltration, suggesting that fractalkine/ tralizing antibodies to Gro-␣/CXCL1 or proliferation of resident monocytes. MCP- CX3CL1is a potent chemoattractant mole- MIP-2/Gro-␤/CXCL2 during renal IRI 1/CCL2, RANTES/CCL5, MIP-1␣/CCL3, cule for macrophages carrying CX3CR1.48,49 blocks interstitial neutrophil infiltration, re- and MIP-1␤/CCL4 are the most com- CCR2 and CX3CR1 are both essential for duces renal damage, and improves sur- monly described chemokines used in the the acute release of macrophages from vival.27,26 Deficiency of IL-23, IL-17A, or recruitment of monocyte/macrophages the for infiltration into in- IL-17 receptor, or the addition of neutraliz- during renal inflammation.11,35 The corre- jured kidney.50 Although ablation of ing antibodies to CXCR2 in mice, attenuates sponding receptors mediate firm adhesion CCR2 and CX3CR1 diminishes macro- neutrophil infiltration in IRI.29,30 During the (CCR1), shape change (CCR2 and CCR5), phage infiltration, MCP-1/CCL2 defi- innate immune response in IRI, neutrophils spreading (CCR2 and CCR5), and trans- ciency exerts no effect on renal macrophage produce a large amount of IL-17A, which in migration.11 infiltration, suggesting the presence of turn induces proinflammatory cytokines and A critical role for chemokine signaling redundancy. Thus, targeting the early macro- chemokine (CXCL1/2) to promote kidney in macrophage infiltration is demon- phagetraffickingbyCCR2andCXC3R1may inflammation. It is known that IL-17 is able strated by a number of functional block- have therapeutic potential for AKI. to strongly repress TNF-␣–stimulated ex- ing experiments. For example, abroga- pression of intraperitoneally-10/CXCL10, I- tion of CCR1 or CCR2 signaling in a TAC/CXCL11, and RANTES/CCL5, but it mouse model of AKI results in reduction ROLE OF CHEMOKINES IN also acts synergistically with TNF-␣ to of interstitial macrophage infiltrates.36,37 CHRONIC KIDNEY DISEASES induce IL-8/CXCL8, Gro-␣/CXCL1, and Delivery of a truncated MCP-1/CCL2 MIP-3␣/CCL20.31 Thus, in addition to protein into mice with IRI also blocks ac- Accumulating data from clinical studies proinflammatory cytokines, IL-17 and tivation of CCR2, thereby inhibiting and animal models support the notion IL-23 signal pathways are new modula- macrophage infiltration.38,39 Interest- that chemokines and their cognate re- tors of chemokine-mediated neutro- ingly, injured kidneys from mice lacking ceptors play a critical role in the recruit- phil infiltration during the innate im- CCR1 also reduce expression of CCR1 li- ment of T cells, macrophages, and den- mune response to IRI, and targeting gands(MIP-1␣/CCL3andRANTES/CCL5), dritic cells during the development of this pathway may be a new approach suggestingtheexistenceofapositivefeedback chronic renal injury (Figure 2).10 Al- for its treatment. loop for chemokine production.36,37 though levels of urinary IL-8/CXCL8 ex-

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cretion are increased in patients in the rophage accumulation in anti-GBM nephri- infiltrating glomeruli and the intersti- acute phase of various forms of glomer- tis and UUO.17,62–65 Thus, upregulation of tium.55,87 In a mouse model of crescentic ulonephritis, a large number of CXCR1- MCP-1/CCL2 and the development of mac- glomerulonephritis, upregulation of re- positive neutrophils are also found in rophage accumulation in chronic kidney dis- nal CCR5 ligands (MIP-1␣/CCL3, MIP- both glomeruli and the tubulointersti- ease may be TGF␤/Smad3–dependent. 1␤/CCL4, and RANTES/CCL5) corre- tium of the patients with membranous A critical role for CCL chemokines in lates with the recruitment of monocytes proliferative glomerulonephritis, lupus progressive renal injury is suggested by and T cells,88,35 suggesting a close link be- nephritis, and crescentic glomerulone- functional blocking studies, including tween the CCL chemokines and cell- phritis.51,11 The functional role of CXCL treatment with neutralizing antibodies mediated immune responses. This no- family in inflammatory kidney disease is to CCL chemokines (MCP-1/CCL2) or tion is further confirmed by finding that clearly demonstrated by the finding that their receptors (CCR2), chemically modi- CCR5 null mice have an increased renal administration of an anti-IL-8/CXCL8 fied chemokines (RANTES/CCL5), trun- Th1 response.88 Because the CCR5 li- antibody to rabbits with an immune cated chemokines (MCP-1/CCL2), or small- gands (MIP-1␣/CCL3 and RANTES/ complex nephritis reduces proteinuria molecule receptor antagonists.10,2,1,66–74 All CCL5) also act through CCR1, blockade and neutrophil recruitment.52 of these studies confirm that blockade of of CCR1 with the pharmacologic CCR1 chemokines results in a suppressive effect antagonist, BX471, significantly reduces Role of CCL and CX3CL on glomerular leukocyte infiltration, pro- renal chemokine expression, T cell infil- Chemokines in Chronic Kidney teinuria, and crescent formation in rodent tration, and glomerular crescent forma- Disease models of glomerulonephritis, tubuloin- tion in CCR5 null mice, indicating that Increasing evidence suggests a switch of terstitial macrophage infiltration, and de- increased renal leukocyte recruitment expression of CXCL chemokines (IL-8/ velopment of diabetic nephropathy.66–74 and subsequent tissue damage in ne- CXCL8) to CCL chemokines (MCP-1/ Furthermore, in type I and type II diabetic phritic mice depend on functional CCL2, RANTES/CCL5) in the transition mouse models, deficiency of MCP-1/ CCR1.88 Thus, CCR5 deficiency aggra- from acute to chronic inflammation CCL2 not only ameliorates renal function vates glomerulonephritis through en- (Figure 2).53 As in AKI, urinary IL-8/ but also reduces macrophage infiltration as hanced CCL3/CCL5-CCR1–driven recruit- CXCL8 levels are increased early, but el- well as renal fibrosis.75,76 ment of T cells and macrophages to the evated urinary MCP-1 levels associate Like AKI, fractalkine/CX3CL1 is also kidney.35 On the other hand, abrogation with progressive renal injury.54,55 In ad- detected in renal biopsies from patients of Th1 signaling by deleting the T-bet dition, enhanced expression of glomeru- with progressive kidney injury.77–79 Frac- gene, a transcription factor for Th1 cells, lar MCP-1/CCL2 and ligands of CCR5 talkine/CX3CL1 and its receptor CX3CR not only attenuates glomerular crescent (including RANTES/CCL5, MIP-1␣/CCL3, are upregulated during renal injury in sev- formation and accumulation of CD4ϩ T and MIP-1ß/CCL4) are detected in patients eral mouse models, including experimen- cells and macrophages, but it also re- with various forms of glomerulonephri- tal folic acid nephropathy, crescentic GN, duces intrarenal expression of RANTES/ tis.56–60 and diabetic nephropathy.80,81,78,82,83,77,9 CCL5, Mig/CXCL9, and CXCR3.89 Increased levels of MCP-1/CCL2 are Treatment with a neutralizing antibody However, injection of Th1 cells in mice also associated with progressive tubuloin- against fractalkine/CX3CL1 improves re- increases renal expression of MCP1/ terstitial disease as tubular epithelial cells are nal damage by blocking crescentic forma- CCL2 and RANTES/CCL5, and causes rich sources of CCL chemokines, including tion and macrophage infiltration in rat progressive albuminuria along with cres- MCP-1/CCL2, RANTES/CCL5, and MIP- nephrotoxic nephritis.84 All these studies cent formation.24 Taken together, CCL 1␣/CCL3.55,61,9 In unilateral ureteral ob- imply there might be an important role for chemokines participate in activating in- struction (UUO) producing fibrosis, up- CCL and CX3CL chemokines in chronic filtrating cells related to Th1 immune re- regulation of tubulointerstitial MCP-1/ renal disease regardless of inciting events. sponses during inflammatory renal in- CCL2 correlates with degree of macrophage jury. infiltration, which is associated with activa- Role of Chemokines in T Cell Furthermore, CXCR3, which is highly ϩ tion of the TGF␤/Smad3 signaling path- Infiltration during Kidney Injury expressed on Th1 CD4 cells, is also re- way.16,17 TGF␤ signals through its down- Increasing evidence also suggests the sponsible for the trafficking of Th1 cells stream mediator, Smad3, to induce MCP-1 functional importance of chemokines into injured tissues because its expres- expression. Thus, mice deficient in Smad7, and their receptors in the recruitment of T sion correlates with elevated levels of urinary an inhibitor of TGF␤/Smad signaling, results cells into the kidney with chronic kidney dis- CXCR3ϩ, CD4ϩ T cells, and upregulation of inenhancedTGF␤/Smad3signalingthrough ease (Figure 2).85,86 MIP-1␣/CCL3 is ele- its ligand, intraperitoneally-10/CXCL10, in which MCP-1/CCL2–dependent macro- vated in the urine and in the crescentic mouse models of systemic lupus ery- phage infiltration and tubulointerstitial fi- lesion in patients with crescentic glomer- thematosus and anti–Thy-1 glomerulo- brosis develop in the UUO kidney.16 In con- ulonephritis, whereas its cognate recep- nephritis.90–92,9 CXCR3 deficiency re- trast, inhibition or loss of TGF␤/Smad3 tors, CCR1 and CCR5, are expressed in duces glomerular damage and T blocks MCP-1 expression and mac- CD3ϩ T cells and CD68ϩ macrophages recruitment in crescentic glomerulone-

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phritis and lupus.93,94 Most importantly, progression in experimental glomerulone- 2. Vielhauer V, Eis V, Schlondorff D, Anders the decrease in T cell recruitment is due phritis. HJ: Identifying chemokines as therapeutic ␥ targets in renal disease: Lessons from an- to reduction of both renal IFN- –pro- In conclusion, results from human tagonist studies and knockout mice. Kid- ducing Th1 cells and IL-17–producing and experimental studies suggest that ney Blood Press Res 27: 226–238, 2004 Th17 cells.93 As CXCR3 is expressed on more than a single T cell subset is in- 3. Segerer S, Nelson PJ, Schlondorff D: the Th17 cells, reduction of Th17 cell in- volved in renal injury.102 Understanding Chemokines, chemokine receptors, and re- filtration may be related to impaired traf- chemokine actions on cross-regulation nal disease: From basic science to patho- physiologic and therapeutic studies. JAm ficking of these cells in CXCR3 null mice, of cell infiltration between Th1, Th17, Soc Nephrol 11: 152–176, 2000 rather than reduction of these cells and Treg cells should enable us to iden- 4. Ruster C, Wolf G: The role of chemokines within injured kidneys.93 As CXCR3 is a tify new therapeutic targets to treat renal and chemokine receptors in diabetic ne- trafficking receptor for both Th1 and injury. phropathy. Front Biosci 13: 944–955, 2008 Th17 cells, CXCR3 is one of the potential 5. Panzer U, Steinmetz OM, Stahl RA, Wolf G: Kidney diseases and chemokines. Curr targets for therapy of T cell–mediated re- Drug Targets 7: 65–80, 2006 nal injury. CONCLUSION 6. Lazennec G, Richmond A: Chemokines and During inflammatory kidney injury, chemokine receptors: New insights into chemokines and their receptors also In summary, evidence from experimen- cancer-related inflammation. Trends Mol demonstrate a strong relationship with tal and clinical studies clearly demon- Med 16: 133–144, 2010 7. Galliera E, Corsi MM, Bonecchi R, Locati M, Tregs. As Tregs have anti-inflammatory strates that chemokines are important Mantovani A: Chemokines as pharmaco- properties, their presence is protective to regulators of leukocyte recruitment dur- logical targets. Mini Rev Med Chem 8: renal injury.95–97 Tregs suppress produc- ing kidney injury. Although interference 638–646, 2008 tion of MIP-1␣/CCL3 by macrophages, with chemokine action holds great prom- 8. Vielhauer V, Anders HJ: Chemokines and which in turn protects against macro- ises for the treatment of inflammatory re- chemokine receptors as therapeutic tar- gets in chronic kidney disease. Front Biosci phage-dependent, lymphocyte-indepen- nal diseases in experimental models, the (Schol Ed) 1: 1–12, 2009 95 dent injury. Studies from CCR7 null chemotactic actions of chemokines in 9. Segerer S, Alpers CE: Chemokines and mice demonstrate that CCR7 on Tregs is both initiation and progression of kidney chemokine receptors in renal pathology. critical for homing of Tregs to lymphoid diseases are much more promiscuous Curr Opin Nephrol Hypertens 12: 243–249, organs and guiding the Tregs to sites of and complicated than we thought.1,2 2003 10. Holdsworth SR, Tipping PG: Leukocytes in antigen-specific activation.98–100 Impor- Thus, much effort is required to further ϩ glomerular injury. Semin Immunopathol 29: tantly, adoptive transfer of CCR7 understand the mechanisms of chemo- 355–374, 2007 Tregs, but not CCR7- Tregs, into CCR7 kine function to develop innovative an- 11. Segerer S, Schlondorff D: Role of chemo- null mice restores Treg numbers in lym- tichemokine therapies for human renal kines for the localization of leukocyte sub- phoid organs and ameliorates disease.100 disease. sets in the kidney. Semin Nephrol 27: 260– 274, 2007 Finally, a recent study in a mouse model 12. Lukacs-Kornek V, Engel D, Tacke F, Kurts of nephrotoxic nephritis shows that C: The role of chemokines and their recep- ϩ CCR6 is expressed on renal FoxP3 , tors in biology. Front Biosci ϩ ACKNOWLEDGMENTS CD4 (Tregs), and IL-17–producing 13: 2238–2252, 2008 CD4ϩ (Th17) cells, but not on IFN-␥– 13. Sanz AB, Sanchez-Nino MD, Ramos AM, This work is supported by grants from Re- Moreno JA, Santamaria B, Ruiz-Ortega M, producing Th1 cells.101 Upregulation of search Grant Council of Hong Kong (RGC Egido J, Ortiz A: NF-{kappa}B in Renal In- the CCR6 ligand, CCL20, also contrib- GRF 768207 and 767508, CUHK5/CRF/09 flammation. J Am Soc Nephrol 21: 1254– utes to T cell recruitment, renal tissue 1262, 2010 to H.Y.L., 464010, 763908 and 764109 to injury, albuminuria, and loss of renal 14. Sanchez-Lopez E, Rayego S, Rodrigues- A.C.C.) and the Chinese University of Hong function. 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