Preventing Peritoneal Dialysis-Associated Fibrosis by Therapeutic Blunting of Peritoneal Toll-Like Receptor Activity

Abstract

Peritoneal dialysis (PD) is an essential daily life-saving treatment for end-stage renal failure. PD therapy is limited by peritoneal inflammation, which leads to peritoneal membrane failure as a result of progressive fibrosis. Peritoneal infections, with the concomitant acute inflammatory response and membrane fibrosis development, worsen PD patient outcomes. Patients who remain infection-free, however, also show evidence of inflammation-induced membrane damage and fibrosis, leading to PD cessation. In this case, uraemia, prolonged exposure to bio-incompatible PD solutions and surgical catheter insertion have been reported to induce sterile peritoneal inflammation and fibrosis as a result of cellular stress or tissue injury. Attempts to reduce inflammation (either infection-induced or sterile) and, thus, minimize fibrosis development in PD have been hampered because the immunological mechanisms underlying this PD-associated pathology remain to be fully defined. Toll-like receptors (TLRs) are central to mediating inflammatory responses by recognizing a wide variety of microorganisms and endogenous components released following cellular stress or generated as a consequence of extracellular matrix degradation during tissue injury. Given the close link between inflammation and fibrosis, recent investigations have evaluated the role that TLRs play in infection-induced and sterile peritoneal fibrosis development during PD. Here, we review the findings and discuss the potential of reducing peritoneal TLR activity by using a TLR inhibitor, soluble TLR2, as a therapeutic strategy to prevent PD-associated peritoneal fibrosis.

Keywords: inflammation; peritoneal dialysis; peritoneal fibrosis; soluble toll-like receptor 2; toll-like receptors.

FIGURE 1

Critical contribution of TLR2 and TLR4 to bacteria-induced peritoneal fibrosis development. (A,B) Wild-type (WT), TLR2 deficient (TLR2^-/-) or TLR4^-/- mice (n = 5 per group) were inoculated intraperitoneally 4 times at weekly intervals with S. epidermidis (S. epi., 5 × 10⁸ CFU/mouse) or Escherichia coli (E. coli, 2 × 10⁷ CFU/mouse) or left untreated (control). Four weeks after the last injection, histological analysis of the peritoneal membrane was conducted and the thickness of the sub-mesothelial compact zone (SMC, layer between the muscle and membrane surface) was determined. Bar plots show the mean ( ± SEM) of SMC thickness in each experimental group. ^∗P < 0.05; ^∗∗∗, P < 0.005. Adapted with permission from Raby et al. (2017).

FIGURE 2

Therapeutic potential of soluble Toll-like receptor 2 (sTLR2) against bacteria- and PD solution-induced peritoneal fibrosis development. (A,B) mice (n = 5 per group) were inoculated intraperitoneally 4 times at weekly intervals with S. epidermidis (S. epi., 5 × 10⁸ CFU/mouse) or Escherichia coli (E. coli, 2 × 10⁷ CFU/mouse) in the presence or absence of sTLR2 (250 ng/mouse), or left untreated (control). Four weeks after the last injection, histological analysis of the peritoneal membrane was conducted and the thickness of the sub-mesothelial compact zone (SMC) was determined. Bar plots show the mean ( ± SEM) of SMC thickness in each experimental group. ^∗ P < 0.05; ^∗∗∗, P < 0.005. (C,D) Mice were instilled twice daily with 2 ml of PBS (n = 5) or Fresenius Standard glucose solution (PDS, n = 8) in the presence or absence of sTLR2 for 40 days before sacrifice, tissue sample collection and histological analysis of the peritoneal membrane for SMC thickness determination. Results show the mean ( ± SEM) for each experimental group. ^∗P < 0.05; ^∗∗P < 0.01. Scatter plots in (D) show the effect of PDS on the expression of fibrosis-related genes in the absence and presence of sTLR2, as assessed by quantitative RT-PCR on RNA extracted from peritoneal membrane samples. Dotted lines indicate the 0.5 and 2 fold change thresholds. Open circles outside the dotted lines correspond to genes modulated in a non-statistically significant manner. Adapted with permission from Raby et al. (2018).