Abstract: TH-PO854

Blunting Toll-Like Receptor Activity with Soluble TLR2 Inhibits PD Solution-Induced Fibrosis

Session Information

  • Peritoneal Dialysis - I
    November 02, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Dialysis

  • 608 Peritoneal Dialysis

Authors

  • Raby, Anne-Catherine, Cardiff University, Cardiff, United Kingdom
  • Gonz?lez- Mateo, Guadalupe T., Molecular Biology Research Centre Severo Ochoa, Spanish Research Council, Madrid, Spain
  • Fraser, Donald, Cardiff University, Cardiff, United Kingdom
  • Lopez-Cabrera, Manuel, Consejo Superior de Investigaciones Cientificas (CSIC). Spain, Madrid, Spain
  • Labéta, Mario O, Cardiff University, Cardiff, United Kingdom
Background

Membrane failure due to fibrosis limits the use of peritoneal dialysis (PD). Fibrosis results from peritoneal inflammation caused by infections or by ongoing cellular stress induced by PD (sterile inflammation). The immune mechanisms involved in sterile peritoneal inflammation leading to fibrosis are still poorly defined. Toll-like receptors (TLRs) mediate sterile inflammation by recognising endogenous components released by cellular stress (DAMPs). We hypothesise that TLRs play a crucial role in sterile inflammation and fibrosis by recognising DAMPs released during PD and, thus, are major therapeutic targets for fibrosis prevention.

Results

A range of PD solutions (PDS) underwent comprehensive in vivo and ex vivo characterisation of TLR-mediated inflammatory and fibrotic mediator production (genes and proteins). All PDS elicited proinflammatory and fibrotic responses from primary human uremic peritoneal leukocytes and mesothelial cells. TLR2/4 blockade inhibited these effects. PDS did not induce rapid ERK phosphorylation, suggesting that they do not contain components capable of direct TLR activation. However, PDS increased the release of Hsp70 and HA from a panel of DAMPs tested, and their blockade repressed PDS-driven inflammation. The peritoneal response to Hsp70 and HA was mediated mainly by TLR4 and to a lesser extent TLR2. Soluble TLR2 (sTLR2), an inhibitor of DAMP-TLR interaction, was found to inhibit Hsp70-, HA- and PDS-induced peritoneal proinflammatory cytokine release. PDS exposure also increased peritoneal Hsp70 and HA in mice, and the use of TLRKO mice confirmed a major role of TLR2/4 in PD solution-induced fibrotic responses. The therapeutic potential of sTLR2 was examined in a mouse model of PDS-induced sterile peritoneal fibrosis. Daily catheter infusion of PDS led to robust peritoneal fibrosis by day 40. Co-administration of sTLR2 prevented peritoneal fibrosis development by suppressing profibrotic gene expression, proinflammatory cytokine production and reducing leukocyte recruitment.

Conclusion

The study reveals a major role of TLR2 and TLR4 in PD solution-associated peritoneal inflammation and fibrosis, identifies Hsp70 and HA as main DAMPs and demonstrates the therapeutic potential of blunting TLR activity to prevent PD solution-induced fibrosis by using a TLR modulator, sTLR2.