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TLR-mediated albuminuria needs TNF α -mediated cooperativity between TLRs present in hematopoietic tissues and CD80 present on non-hematopoietic tissues in mice

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ABSTRACT

Transient albuminuria induced by pathogen-associated molecular patterns (PAMPs) in mice through engagement of Toll-like receptors (TLRs) is widely studied as a partial model for some forms of human nephrotic syndrome (NS). In addition to TLRs, CD80 has been shown to be essential for PAMP-mediated albuminuria. However, the mechanistic relationships between TLRs, CD80 and albuminuria remain unclear. Here, we show that albuminuria and CD80-uria induced in mice by many TLR ligands are dependent on the expression of TLRs and their downstream signalling intermediate MyD88 exclusively in hematopoietic cells and, conversely, on CD80 expression exclusively in non-hematopoietic cells. TNFα is crucial for TLR-mediated albuminuria and CD80-uria, and induces CD80 expression in cultured renal podocytes. IL-10 from hematopoietic cells ameliorates TNFα production, albuminuria and CD80-uria but does not prevent TNFα-mediated induction of podocyte CD80 expression. Chitohexaose, a small molecule originally of parasite origin, mediates TLR4-dependent anti-inflammatory responses, and blocks TLR-mediated albuminuria and CD80-uria through IL-10. Thus, TNFα is a prominent mediator of renal CD80 induction and resultant albuminuria in this model, and small molecules modulating TLR-mediated inflammatory activation might have contributory or adjunct therapeutic potential in some contexts of NS development.

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CD80−/−mice are resistant to LPS- and poly(I:C)-mediated albuminuria. (A) Comparison of urinary albumin:creatinine ratios between B6 and CD80−/− mice given PBS, LPS or poly(I:C) [number of mice per group as follows: B6+PBS=6, B6+LPS=10, B6+p(I:C)=3; CD80−/−=5 in all groups]. (B) Comparison of urinary CD80 levels between B6 and CD80−/− mice given PBS or p(I:C) (five mice per group). (D) Levels of albumin in urine of B6 mice given PBS or Pam3CSK4 (six mice per group). The results represent mean±s.e.m. ND, not detectable.
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DMM023440F1: CD80−/−mice are resistant to LPS- and poly(I:C)-mediated albuminuria. (A) Comparison of urinary albumin:creatinine ratios between B6 and CD80−/− mice given PBS, LPS or poly(I:C) [number of mice per group as follows: B6+PBS=6, B6+LPS=10, B6+p(I:C)=3; CD80−/−=5 in all groups]. (B) Comparison of urinary CD80 levels between B6 and CD80−/− mice given PBS or p(I:C) (five mice per group). (D) Levels of albumin in urine of B6 mice given PBS or Pam3CSK4 (six mice per group). The results represent mean±s.e.m. ND, not detectable.

Mentions: CD80−/− mice have been shown to be resistant to LPS-induced albuminuria (Reiser et al., 2004). We extended these findings to see whether they are resistant to other TLR ligands as well. Wild-type C57BL/6 (B6) and CD80−/− mice were given optimized (100 µg/mouse, intraperitoneally) doses of the TLR4 ligand LPS or the TLR3 ligand polyinosinic:polycytidylic acid [poly(I:C)], and urine was collected 24 h later from individual mice to measure albumin, creatinine and CD80 levels. Although B6 mice showed an elevated albumin:creatinine ratio in urine in response to TLR4 or TLR3 ligation, CD80−/− mice showed no significant change (Fig. 1A). CD80 was detectable in the urine of B6 mice that had been given LPS, but not in its absence (Fig. 1B). CD80-uria in B6 mice was also detected in response to poly(I:C) (Fig. 1C). We also tested Pam3CSK4, a synthetic TLR2 ligand, in B6 mice for its ability to induce albuminuria because, in lupus-prone mice, it is reported to induce albuminuria (Pawar et al., 2009). Similar to ligation of TLR3 and TLR4, TLR2 ligation also resulted in an enhanced albumin:creatinine ratio (Fig. 1D).Fig. 1.


TLR-mediated albuminuria needs TNF α -mediated cooperativity between TLRs present in hematopoietic tissues and CD80 present on non-hematopoietic tissues in mice
CD80−/−mice are resistant to LPS- and poly(I:C)-mediated albuminuria. (A) Comparison of urinary albumin:creatinine ratios between B6 and CD80−/− mice given PBS, LPS or poly(I:C) [number of mice per group as follows: B6+PBS=6, B6+LPS=10, B6+p(I:C)=3; CD80−/−=5 in all groups]. (B) Comparison of urinary CD80 levels between B6 and CD80−/− mice given PBS or p(I:C) (five mice per group). (D) Levels of albumin in urine of B6 mice given PBS or Pam3CSK4 (six mice per group). The results represent mean±s.e.m. ND, not detectable.
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DMM023440F1: CD80−/−mice are resistant to LPS- and poly(I:C)-mediated albuminuria. (A) Comparison of urinary albumin:creatinine ratios between B6 and CD80−/− mice given PBS, LPS or poly(I:C) [number of mice per group as follows: B6+PBS=6, B6+LPS=10, B6+p(I:C)=3; CD80−/−=5 in all groups]. (B) Comparison of urinary CD80 levels between B6 and CD80−/− mice given PBS or p(I:C) (five mice per group). (D) Levels of albumin in urine of B6 mice given PBS or Pam3CSK4 (six mice per group). The results represent mean±s.e.m. ND, not detectable.
Mentions: CD80−/− mice have been shown to be resistant to LPS-induced albuminuria (Reiser et al., 2004). We extended these findings to see whether they are resistant to other TLR ligands as well. Wild-type C57BL/6 (B6) and CD80−/− mice were given optimized (100 µg/mouse, intraperitoneally) doses of the TLR4 ligand LPS or the TLR3 ligand polyinosinic:polycytidylic acid [poly(I:C)], and urine was collected 24 h later from individual mice to measure albumin, creatinine and CD80 levels. Although B6 mice showed an elevated albumin:creatinine ratio in urine in response to TLR4 or TLR3 ligation, CD80−/− mice showed no significant change (Fig. 1A). CD80 was detectable in the urine of B6 mice that had been given LPS, but not in its absence (Fig. 1B). CD80-uria in B6 mice was also detected in response to poly(I:C) (Fig. 1C). We also tested Pam3CSK4, a synthetic TLR2 ligand, in B6 mice for its ability to induce albuminuria because, in lupus-prone mice, it is reported to induce albuminuria (Pawar et al., 2009). Similar to ligation of TLR3 and TLR4, TLR2 ligation also resulted in an enhanced albumin:creatinine ratio (Fig. 1D).Fig. 1.

View Article: PubMed Central - PubMed

ABSTRACT

Transient albuminuria induced by pathogen-associated molecular patterns (PAMPs) in mice through engagement of Toll-like receptors (TLRs) is widely studied as a partial model for some forms of human nephrotic syndrome (NS). In addition to TLRs, CD80 has been shown to be essential for PAMP-mediated albuminuria. However, the mechanistic relationships between TLRs, CD80 and albuminuria remain unclear. Here, we show that albuminuria and CD80-uria induced in mice by many TLR ligands are dependent on the expression of TLRs and their downstream signalling intermediate MyD88 exclusively in hematopoietic cells and, conversely, on CD80 expression exclusively in non-hematopoietic cells. TNFα is crucial for TLR-mediated albuminuria and CD80-uria, and induces CD80 expression in cultured renal podocytes. IL-10 from hematopoietic cells ameliorates TNFα production, albuminuria and CD80-uria but does not prevent TNFα-mediated induction of podocyte CD80 expression. Chitohexaose, a small molecule originally of parasite origin, mediates TLR4-dependent anti-inflammatory responses, and blocks TLR-mediated albuminuria and CD80-uria through IL-10. Thus, TNFα is a prominent mediator of renal CD80 induction and resultant albuminuria in this model, and small molecules modulating TLR-mediated inflammatory activation might have contributory or adjunct therapeutic potential in some contexts of NS development.

No MeSH data available.


Related in: MedlinePlus