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The role of Toll-like receptor 2 in inflammation and fibrosis during progressive renal injury.

Leemans JC, Butter LM, Pulskens WP, Teske GJ, Claessen N, van der Poll T, Florquin S - PLoS ONE (2009)

Bottom Line: We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury.Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-beta in kidneys of TLR2(-/-) mice compared with TLR2(+/+) animals.Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. j.c.leemans@amc.uva.nl

ABSTRACT
Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals. The expression and function of TLR2 during renal fibrosis and chronic inflammation has however not yet been elucidated. Therefore, we studied TLR2 expression in human and murine progressive renal diseases and explored its role by inducing obstructive nephropathy in TLR2(-/-) or TLR2(+/+) mice. We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury. In mice with obstructive nephropathy, renal injury was associated with a marked upregulation and change in distribution of TLR2 and upregulation of murine TLR2 danger ligands Gp96, biglycan, and HMGB1. Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-beta in kidneys of TLR2(-/-) mice compared with TLR2(+/+) animals. Although, the obstructed kidneys of TLR2(-/-) mice had less interstitial myofibroblasts in the later phase of obstructive nephropathy, tubular injury and renal matrix accumulation was similar in both mouse strains. Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis.

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TLR2 expression and localization in renal biopsy specimens of patients with obstructive hydronephrosis (B), severe forms of IgA nephropathy (C, D) or in control renal biopsy specimens (A).TLR2 was clearly upregulated in kidneys of patients with obstructive hydronephrosis or IgA nephropathy and mainly expressed by tubulointerstitial cells. Some expression was found at the apical side of renal tubules (asterisks, D). Double staining showed coexpression of various myofibroblasts (blue) (asterisks E), and numerous macrophages (blue) with TLR2 (red) (asterisks F). No immunoreactivity of TLR2 was observed in negative control sections derived from IgA nephropathy patients (insert A, primary antibody omitted).
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pone-0005704-g001: TLR2 expression and localization in renal biopsy specimens of patients with obstructive hydronephrosis (B), severe forms of IgA nephropathy (C, D) or in control renal biopsy specimens (A).TLR2 was clearly upregulated in kidneys of patients with obstructive hydronephrosis or IgA nephropathy and mainly expressed by tubulointerstitial cells. Some expression was found at the apical side of renal tubules (asterisks, D). Double staining showed coexpression of various myofibroblasts (blue) (asterisks E), and numerous macrophages (blue) with TLR2 (red) (asterisks F). No immunoreactivity of TLR2 was observed in negative control sections derived from IgA nephropathy patients (insert A, primary antibody omitted).

Mentions: Fibrosis and renal atrophy are common outcomes of hydronephrosis due to obstruction. Therefore, we wondered if tubulo-interstitial damage that developed upon obstructive hydronephrosis may be associated with TLR2 expression. Immunohistochemical staining for TLR2 with an Ab that was proven to be highly specific for both murine and human TLR2 [6], [25] revealed a strong increase of TLR2 expression in every one of the four analyzed hydronephrotic obstructed kidneys of patients (Fig 1B) compared to control biopsies without tubular changes and with few TLR2 positive interstitial cells (Fig. 1A). Extensive renal atrophy in end-stage hydronephrotic kidneys made it however impossible to phenotype TLR2-positive cells on histologic sections. Therefore, we analyzed TLR2 expression during chronic IgA nephropathy which is also associated with interstitial fibrosis, tubular atrophy, and interstitial inflammation. Similar to patients with hydronephrosis we found a strong increase of TLR2 expression in all the fifteen analyzed kidneys of IgA nephropathy patients (Fig. 1C and D) compared to control renal biopsy specimens (Fig. 1A). TLR2 was mainly expressed by tubulointerstitial cells and some expression was found at the apical side of renal tubules (asterisks Fig. 1D). Double staining revealed that various interstitial myofibroblasts (blue) (asterisks Fig. 1E) and in particular macrophages (blue) (asterisks Fig. 1F) expressed TLR2 (red). Occasionally, we found granulocytes in renal biopsies with low expression of TLR2 (data not shown).


The role of Toll-like receptor 2 in inflammation and fibrosis during progressive renal injury.

Leemans JC, Butter LM, Pulskens WP, Teske GJ, Claessen N, van der Poll T, Florquin S - PLoS ONE (2009)

TLR2 expression and localization in renal biopsy specimens of patients with obstructive hydronephrosis (B), severe forms of IgA nephropathy (C, D) or in control renal biopsy specimens (A).TLR2 was clearly upregulated in kidneys of patients with obstructive hydronephrosis or IgA nephropathy and mainly expressed by tubulointerstitial cells. Some expression was found at the apical side of renal tubules (asterisks, D). Double staining showed coexpression of various myofibroblasts (blue) (asterisks E), and numerous macrophages (blue) with TLR2 (red) (asterisks F). No immunoreactivity of TLR2 was observed in negative control sections derived from IgA nephropathy patients (insert A, primary antibody omitted).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682651&req=5

pone-0005704-g001: TLR2 expression and localization in renal biopsy specimens of patients with obstructive hydronephrosis (B), severe forms of IgA nephropathy (C, D) or in control renal biopsy specimens (A).TLR2 was clearly upregulated in kidneys of patients with obstructive hydronephrosis or IgA nephropathy and mainly expressed by tubulointerstitial cells. Some expression was found at the apical side of renal tubules (asterisks, D). Double staining showed coexpression of various myofibroblasts (blue) (asterisks E), and numerous macrophages (blue) with TLR2 (red) (asterisks F). No immunoreactivity of TLR2 was observed in negative control sections derived from IgA nephropathy patients (insert A, primary antibody omitted).
Mentions: Fibrosis and renal atrophy are common outcomes of hydronephrosis due to obstruction. Therefore, we wondered if tubulo-interstitial damage that developed upon obstructive hydronephrosis may be associated with TLR2 expression. Immunohistochemical staining for TLR2 with an Ab that was proven to be highly specific for both murine and human TLR2 [6], [25] revealed a strong increase of TLR2 expression in every one of the four analyzed hydronephrotic obstructed kidneys of patients (Fig 1B) compared to control biopsies without tubular changes and with few TLR2 positive interstitial cells (Fig. 1A). Extensive renal atrophy in end-stage hydronephrotic kidneys made it however impossible to phenotype TLR2-positive cells on histologic sections. Therefore, we analyzed TLR2 expression during chronic IgA nephropathy which is also associated with interstitial fibrosis, tubular atrophy, and interstitial inflammation. Similar to patients with hydronephrosis we found a strong increase of TLR2 expression in all the fifteen analyzed kidneys of IgA nephropathy patients (Fig. 1C and D) compared to control renal biopsy specimens (Fig. 1A). TLR2 was mainly expressed by tubulointerstitial cells and some expression was found at the apical side of renal tubules (asterisks Fig. 1D). Double staining revealed that various interstitial myofibroblasts (blue) (asterisks Fig. 1E) and in particular macrophages (blue) (asterisks Fig. 1F) expressed TLR2 (red). Occasionally, we found granulocytes in renal biopsies with low expression of TLR2 (data not shown).

Bottom Line: We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury.Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-beta in kidneys of TLR2(-/-) mice compared with TLR2(+/+) animals.Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. j.c.leemans@amc.uva.nl

ABSTRACT
Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals. The expression and function of TLR2 during renal fibrosis and chronic inflammation has however not yet been elucidated. Therefore, we studied TLR2 expression in human and murine progressive renal diseases and explored its role by inducing obstructive nephropathy in TLR2(-/-) or TLR2(+/+) mice. We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury. In mice with obstructive nephropathy, renal injury was associated with a marked upregulation and change in distribution of TLR2 and upregulation of murine TLR2 danger ligands Gp96, biglycan, and HMGB1. Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-beta in kidneys of TLR2(-/-) mice compared with TLR2(+/+) animals. Although, the obstructed kidneys of TLR2(-/-) mice had less interstitial myofibroblasts in the later phase of obstructive nephropathy, tubular injury and renal matrix accumulation was similar in both mouse strains. Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis.

Show MeSH
Related in: MedlinePlus