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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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Leukocyte influx (A, B) and chemokine (C) levels in kidneys from TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral kidneys.The number of granulocytes (B, t = 3, 7, 14) were significantly lower in TLR2−/− mice compared to TLR2+/+ animals after UUO as counted in 10 randomly selected high-power fields (A, t = 14). No differences were found in the amount of macrophages. Leukocytes were counted in cortex and medulla of renal tissue sections stained for Ly-6G (A: t = 14, B) and F4/80 (B). TLR2−/− mice have furthermore significantly reduced KC (t = 3, 7, 14), and MCP-1 (t = 7) levels in their kidneys as compared to kidneys from TLR2+/+ mice (C). The presence of protein was measured in kidney homogenates by specific ELISA. Data are mean and SEM of six mice per group. *p<0.05.
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pone-0005704-g005: Leukocyte influx (A, B) and chemokine (C) levels in kidneys from TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral kidneys.The number of granulocytes (B, t = 3, 7, 14) were significantly lower in TLR2−/− mice compared to TLR2+/+ animals after UUO as counted in 10 randomly selected high-power fields (A, t = 14). No differences were found in the amount of macrophages. Leukocytes were counted in cortex and medulla of renal tissue sections stained for Ly-6G (A: t = 14, B) and F4/80 (B). TLR2−/− mice have furthermore significantly reduced KC (t = 3, 7, 14), and MCP-1 (t = 7) levels in their kidneys as compared to kidneys from TLR2+/+ mice (C). The presence of protein was measured in kidney homogenates by specific ELISA. Data are mean and SEM of six mice per group. *p<0.05.

Mentions: One of the early events in progressive renal injury is the recruitment of inflammatory cells. Analysis of the influx of granulocytes and macrophages demonstrated that the amount of inflammatory cells increased progressively from day 3 till 14 in obstructed kidneys compared to the contralateral unobstructed kidney (Fig. 5B). The increased leukocyte influx in the tubulointerstitium was accompanied by a strong increase in renal KC (granulocyte attractant), and MCP-1 (monocyte chemoattractant) (Fig. 5C). Interestingly, granulocyte influx was 3, 2.5 and 4.5 times lower in the obstructed kidney of TLR2−/− animals compared with TLR2+/+ mice respectively 3, 7, and 14 days after UUO injury (Fig. 5A,B) as assessed by immunohistochemistry (Fig. 5A, t = 14). In line, we found that the levels of KC (t = 3, t = 7) was significantly lower in the obstructed kidney of TLR2−/− animals compared with TLR2+/+ mice (Fig. 5C). Although no significant differences were found when analyzing macrophage influx (Fig. 5B) we did find lower levels of MCP-1 (t = 7) in TLR2−/− mice compared to TLR2+/+ animals. Together, these results reveal an important role for TLR2 in the induction of a pro-inflammatory immune response during progressive renal injury.


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)

Leukocyte influx (A, B) and chemokine (C) levels in kidneys from TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral kidneys.The number of granulocytes (B, t = 3, 7, 14) were significantly lower in TLR2−/− mice compared to TLR2+/+ animals after UUO as counted in 10 randomly selected high-power fields (A, t = 14). No differences were found in the amount of macrophages. Leukocytes were counted in cortex and medulla of renal tissue sections stained for Ly-6G (A: t = 14, B) and F4/80 (B). TLR2−/− mice have furthermore significantly reduced KC (t = 3, 7, 14), and MCP-1 (t = 7) levels in their kidneys as compared to kidneys from TLR2+/+ mice (C). The presence of protein was measured in kidney homogenates by specific ELISA. 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-g005: Leukocyte influx (A, B) and chemokine (C) levels in kidneys from TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral kidneys.The number of granulocytes (B, t = 3, 7, 14) were significantly lower in TLR2−/− mice compared to TLR2+/+ animals after UUO as counted in 10 randomly selected high-power fields (A, t = 14). No differences were found in the amount of macrophages. Leukocytes were counted in cortex and medulla of renal tissue sections stained for Ly-6G (A: t = 14, B) and F4/80 (B). TLR2−/− mice have furthermore significantly reduced KC (t = 3, 7, 14), and MCP-1 (t = 7) levels in their kidneys as compared to kidneys from TLR2+/+ mice (C). The presence of protein was measured in kidney homogenates by specific ELISA. Data are mean and SEM of six mice per group. *p<0.05.
Mentions: One of the early events in progressive renal injury is the recruitment of inflammatory cells. Analysis of the influx of granulocytes and macrophages demonstrated that the amount of inflammatory cells increased progressively from day 3 till 14 in obstructed kidneys compared to the contralateral unobstructed kidney (Fig. 5B). The increased leukocyte influx in the tubulointerstitium was accompanied by a strong increase in renal KC (granulocyte attractant), and MCP-1 (monocyte chemoattractant) (Fig. 5C). Interestingly, granulocyte influx was 3, 2.5 and 4.5 times lower in the obstructed kidney of TLR2−/− animals compared with TLR2+/+ mice respectively 3, 7, and 14 days after UUO injury (Fig. 5A,B) as assessed by immunohistochemistry (Fig. 5A, t = 14). In line, we found that the levels of KC (t = 3, t = 7) was significantly lower in the obstructed kidney of TLR2−/− animals compared with TLR2+/+ mice (Fig. 5C). Although no significant differences were found when analyzing macrophage influx (Fig. 5B) we did find lower levels of MCP-1 (t = 7) in TLR2−/− mice compared to TLR2+/+ animals. Together, these results reveal an important role for TLR2 in the induction of a pro-inflammatory immune response during progressive renal injury.

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