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• W2002204248 abstract "Mice transgenic for thymic stromal lymphopoietin (TSLP), under regulation of the lymphocyte-specific promoter Lck, develop cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN) similar to the disease in patients. To determine whether infiltrating macrophages, a hallmark of this disease, are deleterious or beneficial in the injury process, we developed Lck-TSLP transgenic mice expressing the human diphtheria toxin receptor (DTR) under control of the monocyte/macrophage-restricted CD11b promoter (Lck-TSLP;CD11b-DTR). Treatment with DT resulted in a marked reduction of monocytes/macrophages in the peritoneal cavity of both CD11b-DTR and Lck-TSLP;CD11b-DTR mice and marked reduction of macrophage infiltration in glomeruli of Lck-TSLP;CD11b-DTR mice. Lck-TSLP;CD11b-DTR mice, with or without toxin treatment, had similar levels of cryoglobulinemia and glomerular immunoglobulin deposition as Lck-TSLP mice. Lck-TSLP;CD11b-DTR mice, treated with toxin, had reduced mesangial matrix expansion, glomerular collagen IV accumulation, expression of the activation marker α-smooth muscle actin and transforming growth factor-β1 in mesangial cells, and proteinuria compared with control mice. Thus, macrophage ablation confers protection in this model and indicates a predominately deleterious role for macrophages in the progression of kidney injury in cryoglobulinemic MPGN. Mice transgenic for thymic stromal lymphopoietin (TSLP), under regulation of the lymphocyte-specific promoter Lck, develop cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN) similar to the disease in patients. To determine whether infiltrating macrophages, a hallmark of this disease, are deleterious or beneficial in the injury process, we developed Lck-TSLP transgenic mice expressing the human diphtheria toxin receptor (DTR) under control of the monocyte/macrophage-restricted CD11b promoter (Lck-TSLP;CD11b-DTR). Treatment with DT resulted in a marked reduction of monocytes/macrophages in the peritoneal cavity of both CD11b-DTR and Lck-TSLP;CD11b-DTR mice and marked reduction of macrophage infiltration in glomeruli of Lck-TSLP;CD11b-DTR mice. Lck-TSLP;CD11b-DTR mice, with or without toxin treatment, had similar levels of cryoglobulinemia and glomerular immunoglobulin deposition as Lck-TSLP mice. Lck-TSLP;CD11b-DTR mice, treated with toxin, had reduced mesangial matrix expansion, glomerular collagen IV accumulation, expression of the activation marker α-smooth muscle actin and transforming growth factor-β1 in mesangial cells, and proteinuria compared with control mice. Thus, macrophage ablation confers protection in this model and indicates a predominately deleterious role for macrophages in the progression of kidney injury in cryoglobulinemic MPGN. Macrophages are key participants in inflammation, phagocytosis, tissue repair, and remodeling.1.Gordon S. The macrophage: past, present and future.Eur J Immunol. 2007; 37: S9-S17Crossref PubMed Scopus (438) Google Scholar, 2.Mosser D.M. Edwards J.P. Exploring the full spectrum of macrophage activation.Nat Rev Immunol. 2008; 8: 958-969Crossref PubMed Scopus (6233) Google Scholar, 3.Martinez F.O. Helming L. Gordon S. Alternative activation of macrophages: an immunologic functional perspective.Annu Rev Immunol. 2009; 27: 451-483Crossref PubMed Scopus (2055) Google Scholar, 4.Duffield J.S. The inflammatory macrophage: a story of Jekyll and Hyde.Clin Sci (Lond). 2003; 104: 27-38Crossref PubMed Scopus (382) Google Scholar They are commonly present in glomerulonephritis (GN), and a large influx of monocytes/macrophages is a particular feature of human cryoglobulinemic membranoproliferative GN (MPGN). Although a characteristic feature of this injury, it is still unknown whether the infiltrating monocytes/macrophages fulfill a predominantly beneficial/reparative role in the evolution of this disease or whether they are predominately effectors or promoters of glomerular injury and sclerosis. We have characterized a mouse model of cryoglobulinemia with consequent development of MPGN, the thymic stromal lymphopoietin (TSLP) transgenic mouse (Lck-TSLP), which overexpresses TSLP and has resultant abnormalities in B-cell development.5.Taneda S. Segerer S. Hudkins K.L. et al.Cryoglobulinemic glomerulonephritis in thymic stromal lymphopoietin transgenic mice.Am J Pathol. 2001; 159: 2355-2369Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 6.Muhlfeld A.S. Segerer S. Hudkins K. et al.Overexpression of complement inhibitor Crry does not prevent cryoglobulin-associated membranoproliferative glomerulonephritis.Kidney Int. 2004; 65: 1214-1223Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 7.Guo S. Kowalewska J. Wietecha T.A. et al.Renin-angiotensin system blockade is renoprotective in immune complex-mediated glomerulonephritis.J Am Soc Nephrol. 2008; 19: 1168-1176Crossref PubMed Scopus (30) Google Scholar Lck-TSLP mice develop mixed cryoglobulinemia and a systemic inflammatory disease that involves kidney, lung, spleen, liver, and skin.5.Taneda S. Segerer S. Hudkins K.L. et al.Cryoglobulinemic glomerulonephritis in thymic stromal lymphopoietin transgenic mice.Am J Pathol. 2001; 159: 2355-2369Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 6.Muhlfeld A.S. Segerer S. Hudkins K. et al.Overexpression of complement inhibitor Crry does not prevent cryoglobulin-associated membranoproliferative glomerulonephritis.Kidney Int. 2004; 65: 1214-1223Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 7.Guo S. Kowalewska J. Wietecha T.A. et al.Renin-angiotensin system blockade is renoprotective in immune complex-mediated glomerulonephritis.J Am Soc Nephrol. 2008; 19: 1168-1176Crossref PubMed Scopus (30) Google Scholar These mice develop a renal disease that closely resembles human cryoglobulinemia-associated MPGN. The glomerular injury is characterized by extensive subendothelial capillary and mesangial immune deposits, marked monocyte/macrophage influx, mesangial cell proliferation and matrix expansion, and capillary wall splitting. The renal lesion is evident from about age 30 days in female mice and rapidly progresses to fully developed MPGN by age 50 days. There are also significant lung,5.Taneda S. Segerer S. Hudkins K.L. et al.Cryoglobulinemic glomerulonephritis in thymic stromal lymphopoietin transgenic mice.Am J Pathol. 2001; 159: 2355-2369Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 6.Muhlfeld A.S. Segerer S. Hudkins K. et al.Overexpression of complement inhibitor Crry does not prevent cryoglobulin-associated membranoproliferative glomerulonephritis.Kidney Int. 2004; 65: 1214-1223Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 7.Guo S. Kowalewska J. Wietecha T.A. et al.Renin-angiotensin system blockade is renoprotective in immune complex-mediated glomerulonephritis.J Am Soc Nephrol. 2008; 19: 1168-1176Crossref PubMed Scopus (30) Google Scholar liver,5.Taneda S. Segerer S. Hudkins K.L. et al.Cryoglobulinemic glomerulonephritis in thymic stromal lymphopoietin transgenic mice.Am J Pathol. 2001; 159: 2355-2369Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 6.Muhlfeld A.S. Segerer S. Hudkins K. et al.Overexpression of complement inhibitor Crry does not prevent cryoglobulin-associated membranoproliferative glomerulonephritis.Kidney Int. 2004; 65: 1214-1223Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 7.Guo S. Kowalewska J. Wietecha T.A. et al.Renin-angiotensin system blockade is renoprotective in immune complex-mediated glomerulonephritis.J Am Soc Nephrol. 2008; 19: 1168-1176Crossref PubMed Scopus (30) Google Scholar and skin lesions.8.Iyoda M. Hudkins K.L. Becker-Herman S. et al.Imatinib suppresses cryoglobulinemia and secondary membranoproliferative glomerulonephritis.J Am Soc Nephrol. 2009; 20: 68-77Crossref PubMed Scopus (33) Google Scholar,9.Taneda S. Hudkins K.L. Cui Y. et al.Growth factor expression in a murine model of cryoglobulinemia.Kidney Int. 2003; 63: 576-590Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Female mice usually die at 60 days to 70 days, presumably from severe lung disease. Male mice have a similar but more slowly evolving course, in which the disease is fully manifest by 120 days.5.Taneda S. Segerer S. Hudkins K.L. et al.Cryoglobulinemic glomerulonephritis in thymic stromal lymphopoietin transgenic mice.Am J Pathol. 2001; 159: 2355-2369Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 6.Muhlfeld A.S. Segerer S. Hudkins K. et al.Overexpression of complement inhibitor Crry does not prevent cryoglobulin-associated membranoproliferative glomerulonephritis.Kidney Int. 2004; 65: 1214-1223Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 7.Guo S. Kowalewska J. Wietecha T.A. et al.Renin-angiotensin system blockade is renoprotective in immune complex-mediated glomerulonephritis.J Am Soc Nephrol. 2008; 19: 1168-1176Crossref PubMed Scopus (30) Google Scholar A number of approaches to delete monocyte/macrophage populations, including the use of anti-macrophage serum and liposome-encapsulated clodronate, has been used to test the importance of monocytes/macrophages in vivo in renal disease processes.10.Kobayashi S. Nishihira J. Watanabe S. et al.Prevention of lethal acute hepatic failure by antimacrophage migration inhibitory factor antibody in mice treated with bacille Calmette-Guerin and lipopolysaccharide.Hepatology. 1999; 29: 1752-1759Crossref PubMed Scopus (71) Google Scholar, 11.Cohen B.J. Danon D. Roth G.S. Wound repair in mice as influenced by age and antimacrophage serum.J Gerontol. 1987; 42: 295-301Crossref PubMed Scopus (55) Google Scholar, 12.D’Souza M.J. Oettinger C.W. Shah A. et al.Macrophage depletion by albumin microencapsulated clodronate: attenuation of cytokine release in macrophage-dependent glomerulonephritis.Drug Dev Ind Pharm. 1999; 25: 591-596Crossref PubMed Scopus (42) Google Scholar Monocyte/macrophage depletion using liposomal clodronate reduced tubulointerstitial inflammation and fibrosis in ischemia/reperfusion injury in the rat and mouse.13.Ko G.J. Boo C.S. Jo S.K. et al.Macrophages contribute to the development of renal fibrosis following ischaemia/reperfusion-induced acute kidney injury.Nephrol Dial Transplant. 2008; 23: 842-852Crossref PubMed Scopus (159) Google Scholar,14.Day Y.J. Huang L. Ye H. et al.Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages.Am J Physiol Renal Physiol. 2005; 288: F722-F731Crossref PubMed Scopus (225) Google Scholar A unique CD11b-DTR transgenic mouse, in which human diphtheria toxin receptor (DTR) is specifically expressed by CD11b-expressing cells, allows conditional ablation of mouse monocytes/macrophages by administration of DT. These mice have been carefully characterized for specificity of ablation, and used to study peritoneal inflammation, kidney fibrosis, kidney repair and regeneration, lung, liver and pancreas injury, wound healing, and atherosclerosis.15.Cailhier J.F. Partolina M. Vuthoori S. et al.Conditional macrophage ablation demonstrates that resident macrophages initiate acute peritoneal inflammation.J Immunol. 2005; 174: 2336-2342Crossref PubMed Scopus (200) Google Scholar, 16.Duffield J.S. Forbes S.J. Constandinou C.M. et al.Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair.J Clin Invest. 2005; 115: 56-65Crossref PubMed Scopus (1281) Google Scholar, 17.Stoneman V. Braganza D. Figg N. et al.Monocyte/macrophage suppression in CD11b diphtheria toxin receptor transgenic mice differentially affects atherogenesis and established plaques.Circ Res. 2007; 100: 884-893Crossref PubMed Scopus (216) Google Scholar, 18.Duffield J.S. Tipping P.G. Kipari T. et al.Conditional ablation of macrophages halts progression of crescentic glomerulonephritis.Am J Pathol. 2005; 167: 1207-1219Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar In a model of rapidly progressive glomerular injury, injection of DT for 5 days, beginning at days 15–20 after a single administration of nephrotoxic serum in CD11b-DTR mice, resulted in markedly reduced glomerular crescents, attenuated tubular injury, and improved renal function.18.Duffield J.S. Tipping P.G. Kipari T. et al.Conditional ablation of macrophages halts progression of crescentic glomerulonephritis.Am J Pathol. 2005; 167: 1207-1219Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar The effect of monocyte/macrophage depletion has not been tested in a model of chronic GN with active and persistent immune complex deposition, such as that occurs in the cryoglobulinemic Lck-TSLP mice and in many patients with MPGN. In this study, we demonstrate that macrophages are essential contributors to the progression of GN and that their presence is a deleterious manifestation of injury. Lck-TSLP mice and CD11b-DTR mice, both on C57BL/6 background, were bred to obtain double-transgenic mice (Lck-TSLP; CD11b-DTR). Cohorts of C57BL6 wild-type (WT), CD11b-DTR, Lck-TSLP, and Lck-TSLP; CD11b-DTR mice were studied with intraperitoneal administration of 20ng/g DT body weight or similar volume of phosphate-buffered saline (PBS) from age days 30–50. CD11b-DTR mice are similar to WT mice with no detectable kidney pathology. The Lck-TSLP; CD11b-DTR mice have similar levels of serum cryoglobulinemia, measured by cryocrits, as to Lck-TSLP mice (data not shown). Both Lck-TSLP and Lck-TSLP; CD11b-DTR mice developed typical features of cryoglobulin-associated MPGN as described previously.5.Taneda S. Segerer S. Hudkins K.L. et al.Cryoglobulinemic glomerulonephritis in thymic stromal lymphopoietin transgenic mice.Am J Pathol. 2001; 159: 2355-2369Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Mice showed progressive kidney injury from age 30 days (Lck-TSLP; CD11b-DTR-30D) to age 50 days, with extensive mesangial cell proliferation and mesangial matrix expansion as demonstrated by increased glomerular tuft area, glomerular hypercellularity, and increased silver methanemine-stained extracellular matrix (Figures 1 and 2). Mesangial cell activation, assessed by α-smooth muscle actin (α-SMA) expression, was also markedly increased.Figure 2Macrophage ablation with diphtheria toxin halts progression of disease as shown by morphometric analysis. (a) Glomerular silver staining matrix; (b) glomerular type IV collagen accumulation; and (c) glomerular α-smooth muscle actin (α-SMA) expression is depicted in wild type (WT), CD11b-DTR mice with DT treatment at 50 days of age, Lck-TSLP; CD11b-DTR mice at 30 days of age, and Lck-TSLP; CD11b-DTR mice at age 50 days, after 20 days of DT or PBS intraperitoneal administration. Lck-TSLP; CD11b-DTR mice treated with diphtheria toxin (DT) have significantly reduced expansion of silver-stained extracellular matrix and glomerular type IV collagen expression compared with the phosphate-buffered saline (PBS) control group. A marker of mesangial cell activation, α-SMA is reduced in Lck-TSLP; CD11b-DTR mice treated with DT compared to those receiving PBS treatment (n=5–6 in each group). *P<0.001, #P<0.01, +P<0.05 versus Lck-TSLP; CD11b-DTR-PBS group. GTA, glomerular tuft area.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Day 50 Lck-TSLP mice show a fivefold increase in glomerular Mφs compared with WT mice: 2.32±0.2 CD68+ cells per glomerular tuft area versus 0.64±0.05 cells in WT mice. In order to gain further insight into the function of these inflammatory macrophages, we characterized them by immunofluorescent staining for recognized markers of M1-type, M2-type, and reparative Mφs (Figure 3, Table 1). Strikingly, the CD68+ cells showed high levels of CD11a expression, Ly6C expression, and a proportion expressed CD40, all markers associated with the M1 activated injurious phenotype. Surprisingly, the vast majority of glomerular Mφs also expressed some markers associated with M2 or wound healing, namely the scavenger receptor CD206 and galectin-3 (M2). However, other M2-type markers such as integrin β5 and transferrin receptor were expressed in a minority. Glycoprotein non-metastatic melanoma B-expressing macrophages have been strongly associated with tissue repair in kidney and liver,19.Li B. Castano A.P. Hudson T.E. et al.The melanoma-associated transmembrane glycoprotein Gpnmb controls trafficking of cellular debris for degradation and is essential for tissue repair.FASEB J. 2010; 24: 4767-4781Crossref PubMed Scopus (106) Google Scholar and a minority of the glomerular Mφs also expressed this marker.Table 1Proportion of CD68+ macrophages (Mφs) in glomerular tuft of Lck-TSLP mice that co-express other markersCD68CD11bCD11aCD40Ly6CGPNMBMac-2TFRCITGB5CD206% CD68+ Mφs100.091.7100.025.075.025.0100.00.050.083.3Standard error50.020.08.325.016.715.00.025.016.7Abbreviations: GPNMB, glycoprotein nonmetastatic melanoma B; ITGB5, integrin B5; TFRC, transferrin receptor; TSLP, thymic stromal lymphopoietin.Examples of co-expression are shown in Figure 3.Data are shown as average±s.e.N=3 mice (10–15 glomeruli/mouse). Open table in a new tab Abbreviations: GPNMB, glycoprotein nonmetastatic melanoma B; ITGB5, integrin B5; TFRC, transferrin receptor; TSLP, thymic stromal lymphopoietin. Examples of co-expression are shown in Figure 3. Data are shown as average±s.e. N=3 mice (10–15 glomeruli/mouse). Flow cytometry analysis of blood monocytes and peritoneal macrophages in Lck-TSLP; CD11b-DTR mice showed that blood monocytes expressing CD11b were reduced in the blood in DT-treated (Lck-TSLP; CD11b-DTR-DT) (2.1±0.6%) mice compared with PBS-treated (Lck-TSLP; CD11b-DTR-PBS) (4.3±0.7%) mice (Table 2). Resident peritoneal macrophages were reduced to 4.5±1.5% of total peritoneal cells in DT-treated mice compared with 22.7±2.6% in PBS-treated Lck-TSLP; CD11b-DTR mice (Table 2). Circulating CD3-expressing T cells were not changed with DT treatment (Table 2).Table 2Ablation of peritoneal macrophages (F4/80-positive) and blood monocytes (CD11b-positive) after administration of DT or PBS to Lck-TSLP; CD11b-DTR miceaPeritoneal lavage and blood are collected 24h after intraperitoneally injected with 20ng/g DT body weight or PBS when the age of mouse is day 30., bData are shown as mean±s.e.m. (n=4 in each group).Peritoneal cavity (% of total cells)CD3F4/80DT3.4±1.24.5±1.0cP<0.05 versus wild-type mice.PBS4.5±1.522.7±2.6Blood (% of leukocytes)CD3CD11bDT3.5±0.82.1±0.6dP<0.001 DT-treated versus PBS-treated Lck-TSLP;CD11b-DTR mice.PBS3.8±0.64.3±0.7Abbreviations: DT, diphtheria toxin; DTR, DT receptor; PBS, phosphate-buffered saline; TSLP, thymic stromal lymphopoietin.a Peritoneal lavage and blood are collected 24h after intraperitoneally injected with 20ng/g DT body weight or PBS when the age of mouse is day 30.b Data are shown as mean±s.e.m. (n=4 in each group).c P<0.05 versus wild-type mice.d P<0.001 DT-treated versus PBS-treated Lck-TSLP;CD11b-DTR mice. Open table in a new tab Abbreviations: DT, diphtheria toxin; DTR, DT receptor; PBS, phosphate-buffered saline; TSLP, thymic stromal lymphopoietin. Both Lck-TSLP and Lck-TSLP; CD11b-DTR mice have remarkable influx of macrophages in glomeruli as measured by immunohistochemistry detection of Mac-2 (galectin-3) and CD68 epitopes (Figure 3). There are few Mac-2- or CD68-expressing cells in the tubulointerstitium in Lck-TSLP and Lck-TSLP; CD11b-DTR mice, and these mice do not develop significant tubular atrophy, tubulointerstitial inflammation, or fibrosis. Lck-TSLP mice treated with either DT or PBS have similar macrophage infiltration in glomeruli. Administration of DT in Lck-TSLP; CD11b-DTR mice resulted in a significant reduction in infiltration of macrophages in glomeruli (Figure 4). A significant reduction in glomerular monocyte/macrophage infiltration was also observed when using another marker of macrophages, CD68 (Figure 4g and h). There was an increase in F4/80-positive cells (a marker expressed by monocyte/macrophages preferentially localized to the tubulointerstitium versus glomeruli) infiltrating the tubulointerstitium in Lck-TSLP; CD11b-DTR mice compared with WT and CD11b-DTR mice (Figure 4i–l). Morphometric analysis demonstrated a trend toward reduction in F4/80-positive interstitial macrophages with DT administration in Lck-TSLP; CD11b-DTR (0.33±0.13% versus 0.17±0.09% positive staining per interstitial area), but results were not statistically significant between any of the groups. There was modest T-cell (CD3+) infiltration in the interstitium, but few T cells in glomeruli in any group. There was no significant difference in glomerular neutrophils assessed by Ly6G expression between the groups (neutrophils/glomerular cross-section: CD11b-DTR-DT: 0.059±0.017; Lck-TSLP; CD11b-DTR-PBS: 0.060±0.009; Lck-TSLP; CD11b-DTR-DT: 0.046±0.008, not significant). C57BL6 WT and CD11b-DTR mice treated with DT for 20 days after age 30 days did not show kidney alterations, and were comparable with PBS-treated control mice. Lck-TSLP mice treated with DT for 20 days after age 30 days developed a progressive GN indistinguishable from that of Lck-TSLP mice treated with PBS. Lck-TSLP; CD11b-DTR mice treated with DT have significantly reduced extracellular matrix expansion compared with Lck-TSLP; CD11b-DTR mice treated with PBS, as measured by silver-stained extracellular matrix (Figures 1 and 2). Type IV collagen, a major component of extracellular matrix, was also significantly reduced in the DT-treated Lck-TSLP; CD11b-DTR group; α-SMA, expressed only by activated mesangial cells, was significantly attenuated by monocyte/macrophage deletion, indicating that glomerular monocyte/macrophages must activate mesangial cells (Figures 1 and 2). Urine albumin excretion increased by fivefold in untreated Lck-TSLP and Lck-TSLP; CD11b-DTR mice at age 30 and 50 days. Macrophage ablation treatment markedly reduced albumin excretion in Lck-TSLP; CD11b-DTR mice (urine albumin/creatinine ratio (μg/mg); Figure 5a). Although the mice have a florid GN, renal function is preserved, as detected by serum blood urea nitrogen. Monocyte/macrophage ablation had no impact on renal function (Figure 5b). Both Lck-TSLP and Lck-TSLP; CD11b-DTR mice express high transforming growth factor (TGF)-β1 transcript levels in the kidney. Monocyte/macrophage ablation decreased the TGF-β1 transcripts in Lck-TSLP; CD11b-DTR mouse kidneys (Figure 6a). Detection of TGF-β1 protein in kidney homogenates by enzyme-linked immunosorbent assay revealed a similar pattern to that of TGF-β1 transcripts: Lck-TSLP; CD11b-DTR mice with monocyte/macrophage ablation have reduced TGF-β1 protein levels compared with Lck-TSLP; CD11b-DTR mice with the normal complement of macrophages (Figure 6b). TGF-β1 expression was restricted to the glomerular mesangium in Lck-TSLP; CD11b-DTR mice (Figure 7a) and monocyte/macrophage ablation decreased protein expression in this region (Figure 7b). Interstitial TGF-β1 was not detected in Lck-TSLP; CD11b-DTR mice. Immunofluorescence analysis showed that Lck-TSLP mice had intense deposition of IgG, IgM, and to a lesser extent of IgA and complement C3 in glomeruli. Monocyte/macrophage ablation did not change the extent or intensity of staining of deposited immunoglobulins and complement C3 (Figure 8). All Lck-TSLP and Lck-TSLP; CD11b-DTR mice had circulating cryoglobulins, whereas WT and CD11b-DTR mice did not. The administration of DT did not change the cryocrit levels (a measurement of plasma cryoglobulin content) in Lck-TSLP or Lck-TSLP; CD11b-DTR mice (data not shown), indicating that ablation did not impact immunoglobulin production or splenic clearance. This is not surprising because splenic macrophages are not ablated in CD11b-DTR mice.15.Cailhier J.F. Partolina M. Vuthoori S. et al.Conditional macrophage ablation demonstrates that resident macrophages initiate acute peritoneal inflammation.J Immunol. 2005; 174: 2336-2342Crossref PubMed Scopus (200) Google Scholar,16.Duffield J.S. Forbes S.J. Constandinou C.M. et al.Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair.J Clin Invest. 2005; 115: 56-65Crossref PubMed Scopus (1281) Google Scholar The cryoglobulinemia in Lck-TSLP or Lck-TSLP; CD11b-DTR mice causes systemic disease, which involves the liver and lung.7.Guo S. Kowalewska J. Wietecha T.A. et al.Renin-angiotensin system blockade is renoprotective in immune complex-mediated glomerulonephritis.J Am Soc Nephrol. 2008; 19: 1168-1176Crossref PubMed Scopus (30) Google Scholar,8.Iyoda M. Hudkins K.L. Becker-Herman S. et al.Imatinib suppresses cryoglobulinemia and secondary membranoproliferative glomerulonephritis.J Am Soc Nephrol. 2009; 20: 68-77Crossref PubMed Scopus (33) Google Scholar Both Lck-TSLP and Lck-TSLP; CD11b-DTR mice have increased liver and lung weights. Histological evaluation of the liver showed periportal leukocyte infiltration in both Lck-TSLP and Lck-TSLP; CD11b-DTR mice.5.Taneda S. Segerer S. Hudkins K.L. et al.Cryoglobulinemic glomerulonephritis in thymic stromal lymphopoietin transgenic mice.Am J Pathol. 2001; 159: 2355-2369Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar,9.Taneda S. Hudkins K.L. Cui Y. et al.Growth factor expression in a murine model of cryoglobulinemia.Kidney Int. 2003; 63: 576-590Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar The lung lesion in Lck-TSLP and Lck-TSLP; CD11b-DTR mice is characterized by marked perivascular and peribronchiolar leukocyte infiltration. As assessed by Mac-2 expression, in the liver, the periportal infiltrating cells are mainly macrophages, whereas only a minority of perivascular and peribronchiolar leukocytes in the lung are macrophages (Figure 9). The hepatic periportal leukocyte infiltration was significantly reduced by administration of DT Lck-TSLP; CD11b-DTR mice (Figure 9 and Table 3). However, DT treatment had no impact on lung macrophage infiltration. Kupffer cells of normal liver and lung alveolar macrophages are also Mac-2-positive, but DT treatment did not affect these myeloid cells (Figure 9).Table 3Semiquantitative grading of lung and liver inflammationaData are shown as mean±s.e.m. (n=6 in each group).Lck-TSLP;CD11b-DTR-30DLck-TSLP;CD11b-DTR-PBSLck-TSLP;CD11b-DTR-DTLung inflammation2.0±0.42.6±0.32.5±0.4Liver inflammation2.2±0.52.4±0.41.5±0.6Abbreviations: DT, diphtheria toxin; DTR, DT receptor; PBS, phosphate-buffered saline; TSLP, thymic stromal lymphopoietin.a Data are shown as mean±s.e.m. (n=6 in each group). Open table in a new tab Abbreviations: DT, diphtheria toxin; DTR, DT receptor; PBS, phosphate-buffered saline; TSLP, thymic stromal lymphopoietin. Monocyte/macrophages are a heterogeneous population of cells, and their effects on different diseases or even on different stages of diseases are often difficult to assess. One unresolved issue in human GN is whether the prominent monocyte/macrophage influx that characterizes cryoglobulinemic MPGN is primarily deleterious and is an effector of disease, or primarily beneficial and involved in disease stabilization and repair. Our study showed that from the time MPGN is first detected (day 30), but when the disease is not advanced, monocyte/macrophages had mainly a detrimental role in disease progression. The specific mechanism by which monocytes/macrophages exert their deleterious effects remains unknown. The elimination of the monocyte-derived cell population had no effect on serum levels of cryoglobulinemia or on the extent of glomerular immune complex deposition. This indicates that the effect of ablation of glomerular macrophage infiltration on the kidney was due to events related to amplification of injury following immune complex deposition, and was unlikely because of a result of immune complex clearance functions performed by these cells. We had speculated that the amplification of injury following glomerular immune complex deposition may occur by activation of infiltrating monocyte/macrophages via their Fc receptors.20.Mosser D.M. The many faces of macrophage activation.J Leukoc Biol. 2003; 73: 209-212Crossref PubMed Scopus (1436) Google Scholar, 21.Mantovani A. Sica A. Locati M. New vistas on macrophage differentiation and activation.Eur J Immunol. 2007; 37: 14-16Crossref PubMed Scopus (315) Google Scholar, 22.Jancar S. Sanchez Crespo M. Immune complex-mediated tissue injury: a multistep paradigm.Trends Immunol. 2005; 26: 48-55Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 23.Kovalenko P. Fujinaka H. Yoshida Y. et al.Fc receptor-mediated accumulation of macrophages in crescentic glomerulonephritis induced by anti-glomerular basement membrane antibody administration in WKY rats.Int Immunol. 2004; 16: 625-634Crossref PubMed Scopus (18) Google Scholar In previous studies of this model, we have shown that genetic deletion of the inhibitory FcγIIb receptor can substantially worsen disease manifestations, which may be due to loss of inhibition of B-cell functions.24.Muhlfeld A.S. Segerer S. Hudkins K. et al.Deletion of the fcgamma receptor IIb in thymic stromal lymphopoietin transgenic mice aggravates membranoproliferative glomerulonephritis.Am J Pathol. 2003; 163: 1127-1136Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Genetic deletion of the FcR γ-chain common to the activating receptors FcγIR, FcγIIIR, and FcγIVR (which results in lack of cell surface expression of these receptors) does not result in an opposite effect of amelioration of MPGN, suggesting" @default.
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