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• W2016775674 abstract "Alternatively activated macrophages (M2) regulate immune responses and ex vivo polarized splenic M2 are able to ameliorate renal injury including models of renal disease, such as adriamycin nephropathy. Whether M2 derived from other organs have similar protective efficacy is unknown. Here, we report adoptively transferred bone marrow M2 macrophages did not improve renal function or reduce renal injury in adriamycin nephropathy, whereas splenic M2 macrophages were protective. Bone marrow and splenic M2 macrophages showed similar regulatory phenotypes and suppressive functions in vitro. Within the inflamed kidney, suppressive phenotypes in bone marrow but not in splenic M2 macrophages, were dramatically reduced. Loss of the suppressive phenotype in bone marrow M2 was related to strong proliferation of bone marrow M2. Bone marrow M2 proliferation in vivo correlated with M-CSF expression by tubular cells in the inflamed kidney. Inhibition of M-CSF in vitro limited bone marrow M2 proliferation and prevented switch of phenotype. Proliferating cells derived from transfused bone marrow M2 were inflammatory rather than regulatory in their phenotype and function. Thus bone marrow in contrast to splenic M2 macrophages do not protect against renal structural and functional injury in murine adriamycin nephropathy. The failed renoprotection of bone marrow M2 is due to the switch of transfused M2 macrophages from a regulatory to an inflammatory phenotype. Alternatively activated macrophages (M2) regulate immune responses and ex vivo polarized splenic M2 are able to ameliorate renal injury including models of renal disease, such as adriamycin nephropathy. Whether M2 derived from other organs have similar protective efficacy is unknown. Here, we report adoptively transferred bone marrow M2 macrophages did not improve renal function or reduce renal injury in adriamycin nephropathy, whereas splenic M2 macrophages were protective. Bone marrow and splenic M2 macrophages showed similar regulatory phenotypes and suppressive functions in vitro. Within the inflamed kidney, suppressive phenotypes in bone marrow but not in splenic M2 macrophages, were dramatically reduced. Loss of the suppressive phenotype in bone marrow M2 was related to strong proliferation of bone marrow M2. Bone marrow M2 proliferation in vivo correlated with M-CSF expression by tubular cells in the inflamed kidney. Inhibition of M-CSF in vitro limited bone marrow M2 proliferation and prevented switch of phenotype. Proliferating cells derived from transfused bone marrow M2 were inflammatory rather than regulatory in their phenotype and function. Thus bone marrow in contrast to splenic M2 macrophages do not protect against renal structural and functional injury in murine adriamycin nephropathy. The failed renoprotection of bone marrow M2 is due to the switch of transfused M2 macrophages from a regulatory to an inflammatory phenotype. Both innate and adaptive immune responses are involved in the inflammatory renal injury of chronic kidney disease (CKD).1.Eddy A.A. Progression in chronic kidney disease.Adv Chronic Kidney Dis. 2005; 12: 353-365Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar, 2.Teteris S.A. Engel D.R. Kurts C. Homeostatic and pathogenic role of renal dendritic cells.Kidney Int. 2011; 80: 139-145Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 3.Anders H.J. Muruve D.A. The inflammasomes in kidney disease.J Am Soc Nephrol. 2011; 22: 1007-1018Crossref PubMed Scopus (285) Google Scholar In some forms of CKD, such as anti-glomerular basement membrane or immune-complex glomerulonephritis (GN), adaptive immunity has a predominant role in mediating renal injury.4.Reynolds J. Prodromidi E.I. Juggapah J.K. et al.Nasal administration of recombinant rat alpha3(IV)NC1 prevents the development of experimental autoimmune glomerulonephritis in the WKY rat.J Am Soc Nephrol. 2005; 16: 1350-1359Crossref PubMed Scopus (37) Google Scholar,5.Heymann F. Meyer-Schwesinger C. Hamilton-Williams E.E. et al.Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury.J Clin Invest. 2009; 119: 1286-1297Crossref PubMed Scopus (178) Google Scholar In other types of CKD, such as focal segmental glomerulosclerosis and diabetic nephropathy, innate immunity predominates.6.Cao Q. Wang C. Zheng D. et al.IL-25 induces M2 macrophages and reduces renal injury in proteinuric kidney disease.J Am Soc Nephrol. 2011; 22: 1229-1239Crossref PubMed Scopus (60) Google Scholar,7.Graves D.T. Kayal R.A. Diabetic complications and dysregulated innate immunity.Front Biosci. 2008; 13: 1227-1239Crossref PubMed Scopus (187) Google Scholar In most types of CKD, renal function and prognosis correlate closely with the extent of mononuclear infiltration of immune cells within the interstitium.8.Ricardo S.D. van Goor H. Eddy A.A. Macrophage diversity in renal injury and repair.J Clin Invest. 2008; 118: 3522-3530Crossref PubMed Scopus (563) Google Scholar,9.Nelson P.J. Rees A.J. Griffin M.D. et al.The renal mononuclear phagocytic system.J Am Soc Nephrol. 2012; 23: 194-203Crossref PubMed Scopus (194) Google Scholar Macrophages are pivotal mediators of glomerular and tubulointerstitial inflammation and fibrosis, owing to their production of proinflammatory cytokines and their ability to induce apoptotic cell death.8.Ricardo S.D. van Goor H. Eddy A.A. Macrophage diversity in renal injury and repair.J Clin Invest. 2008; 118: 3522-3530Crossref PubMed Scopus (563) Google Scholar,10.Sean Eardley K. Cockwell P. Macrophages and progressive tubulointerstitial disease.Kidney Int. 2005; 68: 437-455Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 11.Vernon M.A. Mylonas K.J. Hughes J. Macrophages and renal fibrosis.Semin Nephrol. 2010; 30: 302-317Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 12.Anders H.J. Ryu M. Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis.Kidney Int. 2011; 80: 915-925Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar Adoptive transfer of macrophages has been shown to worsen inflammation in animal models of acute renal injury.13.Lee S. Huen S. Nishio H. et al.Distinct macrophage phenotypes contribute to kidney injury and repair.J Am Soc Nephrol. 2011; 22: 317-326Crossref PubMed Scopus (622) Google Scholar However, in our previous studies, activated macrophages (M1), but not resting macrophages, increased renal injury in murine Adriamycin nephropathy (AN), highlighting the importance of macrophage activation status in causing renal injury.14.Wang Y. Wang Y. Cao Q. et al.By homing to the kidney, activated macrophages potently exacerbate renal injury.Am J Pathol. 2008; 172: 1491-1499Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Macrophages are a heterogeneous population of cells that have a critical role in both host defense and tissue repair.15.Rodriguez Guerrero A. Uchida K. Nakajima H. et al.Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice.J Neuroinflammation. 2012; 9: 40Crossref PubMed Scopus (158) Google Scholar, 16.Marchetti V. Yanes O. Aguilar E. et al.Differential macrophage polarization promotes tissue remodeling and repair in a model of ischemic retinopathy.Sci Rep. 2011; 1: 76Crossref PubMed Scopus (70) Google Scholar, 17.Sica A. Mantovani A. Macrophage plasticity and polarization: in vivo veritas.J Clin Invest. 2012; 122: 787-795Crossref PubMed Scopus (3907) Google Scholar We have found that alternatively activated macrophages (M2) are able to suppress inflammation by deactivating macrophages and inhibiting CD4+ cell proliferation.18.Wang Y. Wang Y.P. Zheng G. et al.Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease.Kidney Int. 2007; 72: 290-299Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar,19.Cao Q. Wang Y. Zheng D. et al.IL-10/TGF-beta-modified macrophages induce regulatory T cells and protect against adriamycin nephrosis.J Am Soc Nephrol. 2010; 21: 933-942Crossref PubMed Scopus (201) Google Scholar Adoptively transferred M2 macrophages can protect against renal structural and functional injury in AN, a robust experimental model of human focal segmental glomerulosclerosis characterized by podocyte injury followed by glomerulosclerosis, tubulointerstitial inflammation, and fibrosis.18.Wang Y. Wang Y.P. Zheng G. et al.Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease.Kidney Int. 2007; 72: 290-299Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar,19.Cao Q. Wang Y. Zheng D. et al.IL-10/TGF-beta-modified macrophages induce regulatory T cells and protect against adriamycin nephrosis.J Am Soc Nephrol. 2010; 21: 933-942Crossref PubMed Scopus (201) Google Scholar Thus, these data demonstrated that the effect of macrophages can cause and worsen immune-related renal injury, whereas alternatively activated macrophages can suppress immune responses and thereby reduce inflammation and enhance recovery of renal injury. Therefore, adoptive transfer of ex vivo–modulated M2 macrophages may prove to be an effective strategy for treating chronic inflammatory renal disease.20.Cao Q. Zheng D. Wang Y.P. et al.Macrophages and dendritic cells for treating kidney disease.Nephron Exp Nephrol. 2011; 117: e47-e52Crossref PubMed Scopus (12) Google Scholar,21.Wang Y. Harris D.C. Macrophages in renal disease.J Am Soc Nephrol. 2011; 22: 21-27Crossref PubMed Scopus (183) Google Scholar In exploring the therapeutic potential of anti-inflammatory macrophages for treating inflammatory renal disease, it is important to examine the efficacy of macrophages from different sources. The protective effect of M2 macrophages derived from spleen has been demonstrated in experimental kidney disease.14.Wang Y. Wang Y. Cao Q. et al.By homing to the kidney, activated macrophages potently exacerbate renal injury.Am J Pathol. 2008; 172: 1491-1499Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar,18.Wang Y. Wang Y.P. Zheng G. et al.Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease.Kidney Int. 2007; 72: 290-299Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar,19.Cao Q. Wang Y. Zheng D. et al.IL-10/TGF-beta-modified macrophages induce regulatory T cells and protect against adriamycin nephrosis.J Am Soc Nephrol. 2010; 21: 933-942Crossref PubMed Scopus (201) Google Scholar However, it is unknown whether M2 macrophages from other sources have similar protective effects. The aim of this study was to examine the effects of adoptive transfer of M2 derived from bone marrow in comparison with M2 derived from spleen. Unexpectedly, our results showed that M2 macrophages from bone marrow, unlike M2 from spleen, did not reduce structural and functional renal injury in AN. The loss of suppressive function of macrophages derived from bone marrow was due to phenotypic changes of transfused M2 in vivo. The phenotypic switch of transferred M2 macrophages from bone marrow was related to their proliferation in inflamed kidney. The expression of CD80, CD86, and B7-H1 of both bone marrow M2 (BM-M2) and splenic M2 (SP-M2) macrophages was increased in comparison with non-modulated macrophages (M0), and there was no significant difference in surface marker expression between BM-M2 and SP-M2 macrophages (Figure 1a). However, BM macrophages, either M0 or M2, expressed higher levels of Gr-1 (a marker highly expressed in bone marrow–derived cells) and CD115 (M-CSF receptor, which is expressed by macrophages and dendritic cells) than splenic macrophages (Figure 1a. Expression of CD115 by BM macrophages was dependent on the dosage of M-CSF, but with splenic macrophages, CD115 expression was not dependent on M-CSF dosage. CD115 expression of BM macrophages reached 95.7% in the presence of 50ng/ml M-CSF (Supplementary Figure S1 online). CD115- BM-M2 macrophages turned into CD115+ BM-M2 macrophages after 4 days of culture with 10ng/ml M-CSF in vitro. CD115- BM-M2 macrophages displayed similar capability of proliferation as did CD115+ BM-M2 macrophages during 14 days of culture (Supplementary Figure S2 online). Download .jpg (.1 MB) Help with files Supplementary Figure S1 Download .jpg (.08 MB) Help with files Supplementary Figure S2 M2 macrophages derived from both BM and spleen expressed higher levels of regulatory molecules such as arginase, MR, YM1, and FIZZ1 compared with M0 macrophages (Figure 1b). There was no difference in those phenotypic markers between BM-M2 and SP-M2 macrophages. Similarly, BM-M2 and SP-M2 macrophages expressed higher levels of IL-10 and TGF-β than did M0 macrophages. There was no increase in TNF-α and IL-12 expression in either BM-M2 or SP-M2 macrophages (Figure 1c). Both BM-M2 and SP-M2 macrophages suppressed T-cell proliferation in comparison with M0, and there was no significant difference in the level of suppression between BM-M2 and SP-M2 macrophages (Figure 1d). CD115- BM-M2 macrophages were similar to CD115+ BM-M2 macrophages in their expression of arginase, MR, IL-10, and TGF-β, and in suppressive functions (Supplementary Figure S3 online). Download .jpg (.08 MB) Help with files Supplementary Figure S3 In mice with AN alone and AN transfused with M0, serum creatinine and proteinuria were significantly increased compared with that of normal mice. Whereas SP-M2 macrophages significantly reduced serum creatinine and proteinuria, BM-M2 macrophages had no effect (Figure 2a and c). Similarly, creatinine clearance was significantly reduced in mice with AN, but was significantly improved in AN mice infused with SP-M2 but not BM-M2 macrophages (Figure 2b). SP-M2 macrophages significantly reduced glomerulosclerosis, tubular damage, and interstitial volume in AN mice, whereas BM-M2 macrophages had no effect (Figure 2d–g). Macrophages labeled with CFSE were distributed to kidney and other organs of AN mice after transfer. Both BM-M2 and SP-M2 macrophages were still seen in kidneys up to day 23 after transfer (Figure 3a and b). The number of transfused BM-M2 macrophages was significantly increased in the AN kidneys at day 23 after transfusion compared with that at day 2 after transfusion, whereas the number of transfused SP-M2 macrophages was not significantly increased in AN kidneys at day 23 after transfusion. There was no significant difference in the number of transfused macrophages in renal draining lymph node (RDLN), spleen, liver, and lung between AN mice transfused with BM-M2 macrophages and those transfused with SP-M2 macrophages (Figure 3c, Supplementary Figure S4 online). Furthermore, there were no significant differences in mRNA expression of CCR1, CCR2, CCR3, CCR5, and CCR7 between BM-M2 and SP-M2 macrophages, whereas CX3CR1 expression was significantly higher in BM-M2 than in SP-M2 macrophages (Figure 3d). Expression of the chemokines CCL2 (MCP-1), CCL5 (RANTES), and IP-10 in AN kidneys increased gradually during week 1, week 2, and week 4 after ADR injection (Figure 3e). Download .jpg (.03 MB) Help with files Supplementary Figure S4 The phenotypes of BM-M2 and SP-M2 macrophages separated from kidneys were examined. The expression of arginase, MR, YM1, FIZZ1, IL-10, and TGF-β mRNA in BM-M2 macrophages decreased significantly from day 7 to day 23 after transfusion, whereas the levels of iNOS, TNF-α, IL-6, and CCL2 increased significantly from day 7 to day 23 (Figure 4a and b). In contrast, the mRNA expression of arginase, MR, YM1, FIZZ1, IL-10, and TGF-β in SP-M2 macrophages was maintained or slightly decreased up to day 23 after transfusion. However, the expression of iNOS, TNF-α, IL-6, and CCL2 mRNA of SP-M2 macrophages increased slightly at day 7 but returned close to the level of fresh SP-M2 macrophages by day 23 (Figure 4c and d). SP-M0 maintained their phenotypes in kidney during the course of disease, but BM-M0 did not (data not shown). The proliferation of macrophages labeled with CFSE was measured by calculating their percentage in kidney and mean fluorescence intensity (MFI) after M2 macrophage transfusion (Figure 5a and b). The percentage of labeled BM-M2 macrophages among kidney cells gradually increased (Figure 5c), whereas the MFI of labeled BM-M2 macrophages gradually decreased from day 2 to day 23 after transfusion, displaying a strong proliferation of BM-M2 macrophages in inflamed kidney (Figure 5d). About 50% of BM-M2 macrophages demonstrated proliferation at 7 days after transfusion and about 90% at 23 days after transfusion. In contrast, SP-M2 macrophages did not show significant proliferation by flow cytometry, and unlike BM-M2 macrophages the percentage and MFI of transfused SP-M2 macrophages in kidney did not change with time (Figure 5c and d). However, the BM-M0 macrophages did proliferate in the kidney, but not in SP-M0 macrophages (data not shown). CFSE-labeled BM-M2 and SP-M2 macrophages were cultured in vitro for 2 weeks, and the proliferated and nonproliferated cells were separated by flow cytometry at week 1 and week 2 (Figure 6a). Proliferated BM-M2 macrophages after 1 or 2 weeks of culture markedly lost their ability to suppress CD4 T-cell proliferation, whereas nonproliferated BM-M2 macrophages maintained their suppressive function. In contrast, SP-M2 macrophages after 1 or 2 weeks of culture maintained their suppressive function (Figure 6b). Proliferated BM-M2 macrophages markedly lost their suppressive phenotype, as seen by the reduction of expression of arginase, MR, IL-10, and TGF-β, whereas nonproliferated BM-M2 macrophages partially maintained their expression levels of arginase, MR, IL-10, and TGF-β (Figure 6c). In addition, SP-M2 macrophages did not proliferate after 1 or 2 weeks of culture and maintained their expression levels of arginase, MR, IL-10, and TGF-β (Figure 6d). Both CD115- BM-M2 and CD115+ BM-M2 macrophages lost their M2 phenotype and suppressive function after proliferation (Supplementary Figure S3 online). Both BM-M2 and SP-M2 macrophages were cultured with a low concentration of M-CSF (2ng/ml) for 2 weeks. The number of BM-M2 macrophages increased up to 80-fold after 2 weeks of culture, whereas the number of SP-M2 macrophages increased less than 5-fold. Proliferation of both BM-M2 and SP-M2 macrophages was significantly blocked by neutralizing anti-M-CSF receptor antibody (Figure 7a and b). The proliferation of BM-M2 macrophages in response to M-CSF was dose dependent (Figure 7c). M-CSF staining appeared in tubule cells at day 2 and increased at day 7 and day 23 after M2 macrophage administration. There is no difference in M-CSF expression between AN mice treated with BM-M2 macrophages and AN mice treated with SP-M2 macrophages (Figure 8a and b). Transfused BM-M2 and SP-M2 macrophages were located mostly in the kidney interstitium, and there were few in the glomeruli. Their distribution was diffuse in the interstitium but also condensed around areas of tubule cells, which expressed M-CSF (Figure 8a). The number of CFSE-labeled BM-M2 macrophages increased progressively from day 2 to day 7 and day 23 after transfusion, but not that of SP-M2 macrophages (Figure 8a and c). The number of interstitial BM-M2 macrophages correlated positively with tubular cell M-CSF expression at day 7 and day 23 after transfusion (Figure 8d and e). In contrast, the number of transfused SP-M2 macrophages did not increase and did not correlate with tubular cell M-CSF expression at day 7 and day 23 after transfusion (Figure 8f and g). To determine whether specific inhibition of macrophage proliferation could maintain M2 phenotype, we explored the effects of GW2580 (a specific inhibitor of c-fms) on macrophage proliferation and phenotype change. BM-M2 macrophages cultured without c-fms blockade showed loss of their suppressive phenotype with reduction of arginase, MR, IL-10, and TGF-β. However, treatment of BM-M2 with GW2580 resulted in a dose-dependent improvement in their suppressive phenotype (Figure 9). Chronic kidney disease (CKD) is a major cause of death and morbidity worldwide. Currently, strategies that successfully delay progression from CKD to end-stage kidney disease are limited and new strategies are needed.1.Eddy A.A. Progression in chronic kidney disease.Adv Chronic Kidney Dis. 2005; 12: 353-365Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar,22.Molony D.A. Stephens B.W. Derangements in phosphate metabolism in chronic kidney diseases/endstage renal disease: therapeutic considerations.Adv Chronic Kidney Dis. 2011; 18: 120-131Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar We have programmed macrophages ex vivo into M2 to treat experimental CKD. Our group first demonstrated that macrophages derived from spleen and modulated with IL-4 and IL-13 ex vivo to induce an M2 phenotype (M2a) were able to reduce renal injury in mice with AN and mice with streptozotocin-induced diabetic nephropathy.18.Wang Y. Wang Y.P. Zheng G. et al.Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease.Kidney Int. 2007; 72: 290-299Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar,23.Zheng D. Wang Y. Cao Q. et al.Transfused macrophages ameliorate pancreatic and renal injury in murine diabetes mellitus.Nephron Exp Nephrol. 2011; 118: e87-e99Crossref PubMed Scopus (64) Google Scholar Similarly, M2c macrophages that were induced ex vivo by IL-10 and TGF-β displayed a marked protective effect against tubular atrophy, interstitial expansion, and proteinuria in AN.19.Cao Q. Wang Y. Zheng D. et al.IL-10/TGF-beta-modified macrophages induce regulatory T cells and protect against adriamycin nephrosis.J Am Soc Nephrol. 2010; 21: 933-942Crossref PubMed Scopus (201) Google Scholar In humans, bone marrow and blood cells are commonly used in cellular therapy. The possibility of using human splenic macrophages in cellular therapy is remote. Therefore, macrophages derived from bone marrow were selected to compare their therapeutic potential with that of splenic macrophages. The initial aim of this study was to compare the potency of SP-M2 macrophages with that of BM-M2 macrophages in AN. Unexpectedly, BM-M2 macrophages, unlike SP-M2 macrophages, had no protective effects against renal functional or histological injury. To be effective, adoptively transferred macrophages need to migrate into the draining lymph nodes or into the diseased inflammatory sites, under the pivotal control of chemokines and chemokine receptors.24.Mantovani A. Sica A. Sozzani S. et al.The chemokine system in diverse forms of macrophage activation and polarization.Trends Immunol. 2004; 25: 677-686Abstract Full Text Full Text PDF PubMed Scopus (4511) Google Scholar, 25.Charo I.F. Ransohoff R.M. The many roles of chemokines and chemokine receptors in inflammation.N Engl J Med. 2006; 354: 610-621Crossref PubMed Scopus (2016) Google Scholar, 26.Vielhauer V. Anders H.J. Chemokines and chemokine receptors as therapeutic targets in chronic kidney disease.Front Biosci (Schol Ed). 2009; 1: 1-12Crossref PubMed Scopus (20) Google Scholar The level of chemokine expression in kidney/lymph nodes and the expression of chemokine receptors on transfused M2 macrophage are likely to affect their migration into the kidney and draining lymph nodes. However, no difference in expression of chemokine receptors was found between SP-M2 and BM-M2 macrophages, except that of CX3CR1, which was more highly expressed in BM-M2 than SP-M2 macrophages but not matched by an increased renal expression of its ligand CX3CL1. Similarly, the expression of chemokine receptors of CCL2, CCL5, and IP-10 showed no difference between SP-M2 and BM-M2 macrophages, regardless of increase of their respective chemokines in kidney. Therefore, the mismatch of upregulated chemokine expression in inflammatory kidney with upregulated M2 macrophage chemokine receptor expression was consistent with a similar migratory capability of BM-M2 and SP-M2 macrophages into inflammatory kidney. Furthermore, in vivo tracking confirmed that equal amounts of transfused SP-M2 and BM-M2 macrophages reached kidneys and kidney draining lymph nodes shortly after transfusion, suggesting that failure of BM-M2 to protect against renal injury was not due to their inability to migrate into kidneys or lymph nodes. Next, we investigated whether or not the failure of BM-M2 macrophages to improve AN could relate to phenotype instability. Indeed, BM-M2 macrophages progressively lost their suppressive features, and expressed an effector (M1) phenotype instead. However, SP-M2 macrophages maintained their M2 phenotype for at least 3 weeks after adoptive transfer. Lee et al. have shown that bone marrow–derived M1 macrophages also can transform into an M2 phenotype during late stages of ischemia/perfusion injury.13.Lee S. Huen S. Nishio H. et al.Distinct macrophage phenotypes contribute to kidney injury and repair.J Am Soc Nephrol. 2011; 22: 317-326Crossref PubMed Scopus (622) Google Scholar This indicates that the plasticity of macrophages depends on the microenvironment of the kidney and can be changed in both directions. Numbers of transfused BM-M2 macrophages were found to increase significantly, but MFI of cells was reduced correspondingly, suggesting that transfused BM-M2 macrophages were proliferated in kidneys. Therefore, we examined the capability of cell proliferation between BM-M2 and SP-M2 macrophages. Certainly, BM-M2 macrophages proliferated continually after transfusion, whereas SP-M2 macrophages did not. It is important to know whether phenotypic instability of BM-M2 macrophages might be related to their proliferation. Interestingly, in vitro and in vivo studies showed that the degree of proliferation of BM-M2 macrophages was associated with their expression levels of suppressive cytokines or regulatory molecules, suggesting that their phenotypic instability was due to cell proliferation. Next, we examined whether the phenotypic instability of BM-M2 macrophages was due to their proliferation. BM-M2 macrophages proliferated partially after 1 week of culture. Proliferated BM-M2 macrophages lost their M2 phenotype, whereas unproliferated BM-M2 macrophages maintained the typical M2 phenotype. There was neither proliferation of SP-M2 macrophages, nor any phenotypic changes. This result indicates strongly that cell proliferation is critical to phenotypic change of macrophages. Further, the relationship between phenotypic change of BM-M2 macrophages and proliferation was demonstrated by blockade of their proliferation. Phenotypic instability of BM-M2 macrophages was prevented by blockade of BM-M2 proliferation with M-CSF antibody. Phenotypic stability of transferred cells in vivo is critical to their therapeutic success. Status of cell maturation has been considered to be a critical factor in the successful use of tolerogenic dendritic cells (DCs) to treat autoimmune diseases or transplant rejection, because tolerogenic DCs are immature and semi-mature, and possibly become mature immunogenic cells under inflammatory conditions.27.Thomson A.W. Robbins P.D. Tolerogenic dendritic cells for autoimmune disease and transplantation.Ann Rheum Dis. 2008; 67: iii90-iii96Crossref PubMed Scopus (105) Google Scholar, 28.Kavousanaki M. Makrigiannakis A. 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In another setting, the failure of cell therapy for cancer has generally been considered to be due to insufficient potency of therapeutic cells.31.Terabe M. Ambrosino E. Takaku S. et al.Synergistic enhancement of CD8+ T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-beta monoclonal antibody.Clin Cancer Res. 2009; 15: 6560-6569Crossref PubMed Scopus (104) Google Scholar, 32.O'Neill D.W. Adams S. Bhardwaj N. Manipulating dendritic cell biology for the active immunotherapy of cancer.Blood. 2004; 104: 2235-2246Crossref PubMed Scopus (295) Google Scholar, 33.Tang S. Moore M.L. Grayson J.M. et al.Increased CD8+" @default.
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• W2016775674 date "2014-04-01" @default.
• W2016775674 modified "2023-10-18" @default.
• W2016775674 title "Failed renoprotection by alternatively activated bone marrow macrophages is due to a proliferation-dependent phenotype switch in vivo" @default.
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• W2016775674 doi "https://doi.org/10.1038/ki.2013.341" @default.
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