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A role for macrophages in mediating tubular cell apoptosis?
Kidney International, Vol. 63 (2003), pp. 1582–1583
EDITORIAL
A role for macrophages in mediating tubular cell apoptosis? Glomerular, and in particular, interstitial macrophage accumulation is a prominent feature in most types of glomerulonephritis [1]. Interstitial macrophage accumulation correlates with renal dysfunction and tubulointerstitial lesions in glomerulonephritis and is predictive of disease progression in lupus nephritis and immunoglobulin A (IgA) nephropathy [1–3], suggesting that these cells contribute to progressive renal damage. Indeed, macrophage accumulation is frequently present in areas of tubular atrophy and active fibrosis. However, macrophages have the potential to both cause renal injury and to promote renal repair. Indeed, the wide variety of macrophage responses to different stimuli indicates that macrophage function is likely to be dictated by the microenvironment in which the cell finds itself. Thus, although it has recently been shown that macrophages can induce acute renal injury in terms of proteinuria and mesangial cell proliferation [4], it does not necessarily follow that interstitial macrophages cause progressive tubulointerstitial damage. There are at least three possible mechanisms through which macrophages may induce tubulointerstitial damage. First, macrophages may cause tubular and capillary cell cytotoxicity through production of mediators such as tumor necrosis factor-␣ (TNF-␣), reactive oxygen species, and nitric oxide. Second, macrophages may promote interstitial accumulation of myofibroblasts by production of chemotactic factors and growth factors such as platelet-derived growth factor and fibroblast growth factor-2 (FGF-2), and by the induction of tubular epithelial cell transdifferentiation into myofibroblasts via secretion of transforming growth factor-1 (TGF-1). Third, macrophages may promote extracellular matrix deposition by myofibroblasts and tubular epithelial cells through production of profibrotic factors TGF-1 and FGF-2. The role of macrophages in progressive tubulointerstitial damage has remained ambiguous since it is technically difficulty to achieve specific and prolonged macrophage depletion in animal disease models. Interstitial macrophage accumulation correlates with tubulointerstitial lesions in human glomerulonephritis [5], and interstitial macrophages are associated with tubular cell apoptosis in a number of animal disease models [6–8]. Consistent with these observations, macrophages can secrete moleKey words: macrophage, tubular cell, apoptosis, anoikis, MMP, myofibroblast.
2003 by the International Society of Nephrology
cules capable of inducing apoptosis of tubular epithelial cells in vitro [8]. However, manipulations that inhibit interstitial myofibroblast accumulation and fibrosis also reduce interstitial macrophage accumulation and tubular apoptosis [9–11], making it difficult to tease out any specific contribution by macrophages to the induction of tubular cell apoptosis. In this issue of Kidney International, Rodgers et al [12] have investigated the role of macrophages in tubulointerstitial damage in mice deficient in the ␣3(IV) collagen gene. These mice develop renal disease that has many similarities to that of Alport syndrome. The study takes advantage of the unique observation that blockade of TGF-1, via administration of a soluble form of the TGF-1 receptor, largely abolishes interstitial myofibroblast accumulation and fibrosis without affecting interstitial macrophage accumulation or tubular cell apoptosis and atrophy. Having ruled out the contribution of TGF-1 and interstitial fibrosis, what is the cause of this relentless tubular apoptosis and atrophy? Rodgers et al [12] favor the hypothesis that interstitial macrophages induce tubular apoptosis in the Alport mouse. They show that interstitial macrophages express matrix metalloproteinase (MMP) 2 and 9, that MMP-2 and MMP-9 are in an active form, and that there is degradation of the tubular basement membrane (TBM) in areas of focal macrophage accumulation. This suggests that macrophages may cause tubular cell apoptosis via degradation of the TBM, leading to tubular cell detachment and the induction of programmed cell death (a process termed anoikis). The postulate that interstitial macrophages cause tubular apoptosis in the Alport mouse through MMPmediated anoikis is certainly an attractive hypothesis with strong supporting data. However, the data are associative in nature and do not prove a causal role for macrophage-mediated tubular cell anoikis. A number of other factors may also play an important role in tubular apoptosis in this disease model. Macrophages have the potential to induce tubular cell apoptosis via the secretion of cytokines such as interferon-␥ or TNF-␣ [13, 14]. The loss of peritubular capillaries, which itself may be due to macrophage-mediated damage, could lead to tubular cell apoptosis via chronic ischemia [15]. In addition, the ␣3(IV) collagen chain is present in a portion of the TBM in normal kidney and its absence in the Alport mouse could result in a subtle TBM abnormality that
1582
Editorial
either directly leads to anoikis or makes the TBM more susceptible to degradation. The hypothesis that macrophages cause tubular cell apoptosis via MMP-dependent anoikis predicts that crossbreeding of Alport mice with MMP-9–deficient mice should reduce tubular apoptosis and atrophy. However, MMP-9–deficient Alport mice are not protected from progressive renal disease [16], although tubular apoptosis was not specifically examined in this study. In addition, MMP-9 gene deficiency has been shown to markedly exacerbate tubular damage and interstitial lesions in mouse anti-glomerular basement membrane (GBM) glomerulonephritis, suggesting that this proteinase has a protective role in suppressing tubulointerstitial damage [17]. A second issue raised by Rodgers et al [12] is the role of macrophages in mediating TGF-1–dependent interstitial myofibroblast accumulation in the Alport mouse. This is based upon a close temporal relationship between interstitial macrophage and myofibroblast accumulation, and the finding that interstitial macrophages contain TGF-1 mRNA and protein. However, caution is needed for this interpretation since tubular cells are also an important source of TGF-1 in the damaged tubulointerstitium in this and other disease models [18, 19], and it is possible to inhibit myofibroblast accumulation in the obstructed kidney without affecting interstitial macrophage infiltration [20]. In conclusion, the study opens up an interesting hypothesis that macrophage-induced tubular cell apoptosis, via MMP-dependent destruction of the TBM, is an important mechanism in progressive interstitial damage leading to end-stage renal failure. Further studies are warranted to address the direct functional role of macrophages, and in particular MMP activity, in this process. David J. Nikolic-Paterson Clayton, Victoria, Australia Correspondence to Dr. David J Nikolic-Paterson, Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail: [email protected]
REFERENCES 1. Nikolic-Paterson DJ, Lan HY, Atkins RC: Macrophages in immune renal injury, in Immunologic Renal Disease, 2nd Edition, edited by Neilson EG, Couser WG, Philadelphia, Lippincott, Williams & Wilkins, 2001, pp 609–632
1583
2. Alexopoulos E, Seron D, Hartley RB, Cameron JS: Lupus nephritis: Correlation of interstitial cells with glomerular function. Kidney Int 37:100–109, 1990 3. Ootaka T, Saito T, Yusa A, et al: Contribution of cellular infiltration to the progression of IgA nephropathy: A longitudinal, immunocytochemical study on repeated renal biopsy specimens. Nephrology 1:135–142, 1995 4. Ikezumi Y, Hurst LA, Masaki T, et al: Adoptive transfer studies demonstrate that macrophages can induce proteinuria and mesangial cell proliferation. Kidney Int 63:83–95, 2003 5. Yang N, Isbel NM, Nikolic-Paterson DJ, et al: Local macrophage proliferation in human glomerulonephritis. Kidney Int 54:143–151, 1998 6. Lange-Sperandio B, Cachat F, Thornhill BA, Chevalier RL: Selectins mediate macrophage infiltration in obstructive nephropathy in newborn mice. Kidney Int 61:516–524, 2002 7. Bankovic-Calic N, Eddy A, Sareen S, Ogborn MR: Renal remodelling in dietary protein modified rat polycystic kidney disease. Pediatr Nephrol 13:567–570, 1999 8. Tesch GH, Schwarting A, Kinoshita K, et al: Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis. J Clin Invest 103:73–80, 1999 9. Mizuno S, Kurosawa T, Matsumoto K, et al: Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal disease. J Clin Invest 101:1827–1834, 1998 10. Miyajima A, Chen J, Lawrence C, et al: Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int 58:2301–2313, 2000 11. Kelly DJ, Cox AJ, Tolcos M, et al: Attenuation of tubular apoptosis by blockade of the renin-angiotensin system in diabetic Ren-2 rats. Kidney Int 61:31–39, 2002 12. Rodgers KD, Rao V, Meehan DT, et al: Monocytes may promote myofibroblast accumulation and apoptosis in Alport renal fibrosis. Kidney Int 63:1338–1355, 2003 13. Schwarting A, Wada T, Kinoshita K, et al: IFN-gamma receptor signaling is essential for the initiation, acceleration, and destruction of autoimmune kidney disease in MRL-Fas(lpr) mice. J Immunol 161:494–503, 1998 14. Tsuruya K, Ninomiya T, Tokumoto M, et al: Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death. Kidney Int 63:72–82, 2003 15. Thomas SE, Anderson S, Gordon KL, et al: Tubulointerstitial disease in aging: Evidence for underlying peritubular capillary damage, a potential role for renal ischemia. J Am Soc Nephrol 9:231–242, 1998 16. Andrews KL, Betsuyaku T, Rogers S, et al: Gelatinase B (MMP-9) is not essential in the normal kidney and does not influence progression of renal disease in a mouse model of Alport syndrome. Am J Pathol 157:303–311, 2000 17. Lelongt B, Bengatta S, Delauche M, et al: Matrix metalloproteinase 9 protects mice from anti-glomerular basement membrane nephritis through its fibrinolytic activity. J Exp Med 193:793–802, 2001 18. Sayers R, Kalluri R, Rodgers KD, et al: Role for transforming growth factor-beta1 in alport renal disease progression. Kidney Int 56:1662–1673, 1999 19. Yang J, Liu Y: Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis. J Am Soc Nephrol 13:96–107, 2002 20. Ishidoya S, Morrissey J, McCracken R, et al: Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Kidney Int 47:1285–1294, 1995
EDITORIAL
A role for macrophages in mediating tubular cell apoptosis? Glomerular, and in particular, interstitial macrophage accumulation is a prominent feature in most types of glomerulonephritis [1]. Interstitial macrophage accumulation correlates with renal dysfunction and tubulointerstitial lesions in glomerulonephritis and is predictive of disease progression in lupus nephritis and immunoglobulin A (IgA) nephropathy [1–3], suggesting that these cells contribute to progressive renal damage. Indeed, macrophage accumulation is frequently present in areas of tubular atrophy and active fibrosis. However, macrophages have the potential to both cause renal injury and to promote renal repair. Indeed, the wide variety of macrophage responses to different stimuli indicates that macrophage function is likely to be dictated by the microenvironment in which the cell finds itself. Thus, although it has recently been shown that macrophages can induce acute renal injury in terms of proteinuria and mesangial cell proliferation [4], it does not necessarily follow that interstitial macrophages cause progressive tubulointerstitial damage. There are at least three possible mechanisms through which macrophages may induce tubulointerstitial damage. First, macrophages may cause tubular and capillary cell cytotoxicity through production of mediators such as tumor necrosis factor-␣ (TNF-␣), reactive oxygen species, and nitric oxide. Second, macrophages may promote interstitial accumulation of myofibroblasts by production of chemotactic factors and growth factors such as platelet-derived growth factor and fibroblast growth factor-2 (FGF-2), and by the induction of tubular epithelial cell transdifferentiation into myofibroblasts via secretion of transforming growth factor-1 (TGF-1). Third, macrophages may promote extracellular matrix deposition by myofibroblasts and tubular epithelial cells through production of profibrotic factors TGF-1 and FGF-2. The role of macrophages in progressive tubulointerstitial damage has remained ambiguous since it is technically difficulty to achieve specific and prolonged macrophage depletion in animal disease models. Interstitial macrophage accumulation correlates with tubulointerstitial lesions in human glomerulonephritis [5], and interstitial macrophages are associated with tubular cell apoptosis in a number of animal disease models [6–8]. Consistent with these observations, macrophages can secrete moleKey words: macrophage, tubular cell, apoptosis, anoikis, MMP, myofibroblast.
2003 by the International Society of Nephrology
cules capable of inducing apoptosis of tubular epithelial cells in vitro [8]. However, manipulations that inhibit interstitial myofibroblast accumulation and fibrosis also reduce interstitial macrophage accumulation and tubular apoptosis [9–11], making it difficult to tease out any specific contribution by macrophages to the induction of tubular cell apoptosis. In this issue of Kidney International, Rodgers et al [12] have investigated the role of macrophages in tubulointerstitial damage in mice deficient in the ␣3(IV) collagen gene. These mice develop renal disease that has many similarities to that of Alport syndrome. The study takes advantage of the unique observation that blockade of TGF-1, via administration of a soluble form of the TGF-1 receptor, largely abolishes interstitial myofibroblast accumulation and fibrosis without affecting interstitial macrophage accumulation or tubular cell apoptosis and atrophy. Having ruled out the contribution of TGF-1 and interstitial fibrosis, what is the cause of this relentless tubular apoptosis and atrophy? Rodgers et al [12] favor the hypothesis that interstitial macrophages induce tubular apoptosis in the Alport mouse. They show that interstitial macrophages express matrix metalloproteinase (MMP) 2 and 9, that MMP-2 and MMP-9 are in an active form, and that there is degradation of the tubular basement membrane (TBM) in areas of focal macrophage accumulation. This suggests that macrophages may cause tubular cell apoptosis via degradation of the TBM, leading to tubular cell detachment and the induction of programmed cell death (a process termed anoikis). The postulate that interstitial macrophages cause tubular apoptosis in the Alport mouse through MMPmediated anoikis is certainly an attractive hypothesis with strong supporting data. However, the data are associative in nature and do not prove a causal role for macrophage-mediated tubular cell anoikis. A number of other factors may also play an important role in tubular apoptosis in this disease model. Macrophages have the potential to induce tubular cell apoptosis via the secretion of cytokines such as interferon-␥ or TNF-␣ [13, 14]. The loss of peritubular capillaries, which itself may be due to macrophage-mediated damage, could lead to tubular cell apoptosis via chronic ischemia [15]. In addition, the ␣3(IV) collagen chain is present in a portion of the TBM in normal kidney and its absence in the Alport mouse could result in a subtle TBM abnormality that
1582
Editorial
either directly leads to anoikis or makes the TBM more susceptible to degradation. The hypothesis that macrophages cause tubular cell apoptosis via MMP-dependent anoikis predicts that crossbreeding of Alport mice with MMP-9–deficient mice should reduce tubular apoptosis and atrophy. However, MMP-9–deficient Alport mice are not protected from progressive renal disease [16], although tubular apoptosis was not specifically examined in this study. In addition, MMP-9 gene deficiency has been shown to markedly exacerbate tubular damage and interstitial lesions in mouse anti-glomerular basement membrane (GBM) glomerulonephritis, suggesting that this proteinase has a protective role in suppressing tubulointerstitial damage [17]. A second issue raised by Rodgers et al [12] is the role of macrophages in mediating TGF-1–dependent interstitial myofibroblast accumulation in the Alport mouse. This is based upon a close temporal relationship between interstitial macrophage and myofibroblast accumulation, and the finding that interstitial macrophages contain TGF-1 mRNA and protein. However, caution is needed for this interpretation since tubular cells are also an important source of TGF-1 in the damaged tubulointerstitium in this and other disease models [18, 19], and it is possible to inhibit myofibroblast accumulation in the obstructed kidney without affecting interstitial macrophage infiltration [20]. In conclusion, the study opens up an interesting hypothesis that macrophage-induced tubular cell apoptosis, via MMP-dependent destruction of the TBM, is an important mechanism in progressive interstitial damage leading to end-stage renal failure. Further studies are warranted to address the direct functional role of macrophages, and in particular MMP activity, in this process. David J. Nikolic-Paterson Clayton, Victoria, Australia Correspondence to Dr. David J Nikolic-Paterson, Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail: [email protected]
REFERENCES 1. Nikolic-Paterson DJ, Lan HY, Atkins RC: Macrophages in immune renal injury, in Immunologic Renal Disease, 2nd Edition, edited by Neilson EG, Couser WG, Philadelphia, Lippincott, Williams & Wilkins, 2001, pp 609–632
1583
2. Alexopoulos E, Seron D, Hartley RB, Cameron JS: Lupus nephritis: Correlation of interstitial cells with glomerular function. Kidney Int 37:100–109, 1990 3. Ootaka T, Saito T, Yusa A, et al: Contribution of cellular infiltration to the progression of IgA nephropathy: A longitudinal, immunocytochemical study on repeated renal biopsy specimens. Nephrology 1:135–142, 1995 4. Ikezumi Y, Hurst LA, Masaki T, et al: Adoptive transfer studies demonstrate that macrophages can induce proteinuria and mesangial cell proliferation. Kidney Int 63:83–95, 2003 5. Yang N, Isbel NM, Nikolic-Paterson DJ, et al: Local macrophage proliferation in human glomerulonephritis. Kidney Int 54:143–151, 1998 6. Lange-Sperandio B, Cachat F, Thornhill BA, Chevalier RL: Selectins mediate macrophage infiltration in obstructive nephropathy in newborn mice. Kidney Int 61:516–524, 2002 7. Bankovic-Calic N, Eddy A, Sareen S, Ogborn MR: Renal remodelling in dietary protein modified rat polycystic kidney disease. Pediatr Nephrol 13:567–570, 1999 8. Tesch GH, Schwarting A, Kinoshita K, et al: Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis. J Clin Invest 103:73–80, 1999 9. Mizuno S, Kurosawa T, Matsumoto K, et al: Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal disease. J Clin Invest 101:1827–1834, 1998 10. Miyajima A, Chen J, Lawrence C, et al: Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int 58:2301–2313, 2000 11. Kelly DJ, Cox AJ, Tolcos M, et al: Attenuation of tubular apoptosis by blockade of the renin-angiotensin system in diabetic Ren-2 rats. Kidney Int 61:31–39, 2002 12. Rodgers KD, Rao V, Meehan DT, et al: Monocytes may promote myofibroblast accumulation and apoptosis in Alport renal fibrosis. Kidney Int 63:1338–1355, 2003 13. Schwarting A, Wada T, Kinoshita K, et al: IFN-gamma receptor signaling is essential for the initiation, acceleration, and destruction of autoimmune kidney disease in MRL-Fas(lpr) mice. J Immunol 161:494–503, 1998 14. Tsuruya K, Ninomiya T, Tokumoto M, et al: Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death. Kidney Int 63:72–82, 2003 15. Thomas SE, Anderson S, Gordon KL, et al: Tubulointerstitial disease in aging: Evidence for underlying peritubular capillary damage, a potential role for renal ischemia. J Am Soc Nephrol 9:231–242, 1998 16. Andrews KL, Betsuyaku T, Rogers S, et al: Gelatinase B (MMP-9) is not essential in the normal kidney and does not influence progression of renal disease in a mouse model of Alport syndrome. Am J Pathol 157:303–311, 2000 17. Lelongt B, Bengatta S, Delauche M, et al: Matrix metalloproteinase 9 protects mice from anti-glomerular basement membrane nephritis through its fibrinolytic activity. J Exp Med 193:793–802, 2001 18. Sayers R, Kalluri R, Rodgers KD, et al: Role for transforming growth factor-beta1 in alport renal disease progression. Kidney Int 56:1662–1673, 1999 19. Yang J, Liu Y: Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis. J Am Soc Nephrol 13:96–107, 2002 20. Ishidoya S, Morrissey J, McCracken R, et al: Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Kidney Int 47:1285–1294, 1995