Limits...
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.

Show MeSH

Related in: MedlinePlus

Quantitative analysis of the amount of interstitial myofibroblasts (α-SMA) in TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral non-obstructed kidneys as a cellular marker of fibrosis (A).This revealed that the amount of α-SMA was increased during UUO and was significantly lower in kidney of TLR2−/− mice compared with TLR2+/+ animals 14 days after UUO-induced injury. The percentage of positive staining for myofibroblasts was analyzed in both cortex and medulla using a computer-assisted digital analysis program on renal tissue sections stained for α-SMA (B: t = 14). Data are mean and SEM of six mice per group, *p<0.05.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2682651&req=5

pone-0005704-g006: Quantitative analysis of the amount of interstitial myofibroblasts (α-SMA) in TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral non-obstructed kidneys as a cellular marker of fibrosis (A).This revealed that the amount of α-SMA was increased during UUO and was significantly lower in kidney of TLR2−/− mice compared with TLR2+/+ animals 14 days after UUO-induced injury. The percentage of positive staining for myofibroblasts was analyzed in both cortex and medulla using a computer-assisted digital analysis program on renal tissue sections stained for α-SMA (B: t = 14). Data are mean and SEM of six mice per group, *p<0.05.

Mentions: To further explore the role of TLR2 during obstructive nephropathy, we additionally analyzed the amount of myofibroblasts (α-SMA). This showed that the amount of myofibroblasts was significantly increased 3 days post-UUO and continued to increase at later time points. Interestingly, significantly less myofibroblasts accumulated in the renal peritubular interstitium of TLR2−/− mice compared with TLR2+/+ animals 14 days after UUO-injury (Fig. 6).


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)

Quantitative analysis of the amount of interstitial myofibroblasts (α-SMA) in TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral non-obstructed kidneys as a cellular marker of fibrosis (A).This revealed that the amount of α-SMA was increased during UUO and was significantly lower in kidney of TLR2−/− mice compared with TLR2+/+ animals 14 days after UUO-induced injury. The percentage of positive staining for myofibroblasts was analyzed in both cortex and medulla using a computer-assisted digital analysis program on renal tissue sections stained for α-SMA (B: t = 14). Data are mean and SEM of six mice per group, *p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0005704-g006: Quantitative analysis of the amount of interstitial myofibroblasts (α-SMA) in TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral non-obstructed kidneys as a cellular marker of fibrosis (A).This revealed that the amount of α-SMA was increased during UUO and was significantly lower in kidney of TLR2−/− mice compared with TLR2+/+ animals 14 days after UUO-induced injury. The percentage of positive staining for myofibroblasts was analyzed in both cortex and medulla using a computer-assisted digital analysis program on renal tissue sections stained for α-SMA (B: t = 14). Data are mean and SEM of six mice per group, *p<0.05.
Mentions: To further explore the role of TLR2 during obstructive nephropathy, we additionally analyzed the amount of myofibroblasts (α-SMA). This showed that the amount of myofibroblasts was significantly increased 3 days post-UUO and continued to increase at later time points. Interestingly, significantly less myofibroblasts accumulated in the renal peritubular interstitium of TLR2−/− mice compared with TLR2+/+ animals 14 days after UUO-injury (Fig. 6).

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