Targeting Toll-like receptors with soluble Toll-like receptor 2 prevents peritoneal dialysis solution–induced fibrosis

Abstract

Peritoneal membrane failure due to fibrosis limits the use of peritoneal dialysis (PD). Peritoneal fibrosis may potentially be induced by sterile inflammation caused by ongoing cellular stress due to prolonged exposure to PD solutions (PDS). Effective therapies to prevent this process remain to be developed. Toll-like receptors (TLRs) mediate sterile inflammation by recognizing damage-associated molecular patterns (DAMPs) released by cellular stress. We evaluated the involvement of TLRs and DAMPs in PDS-induced fibrosis models and the therapeutic potential of TLR-DAMP targeting for preventing fibrosis. A range of PDS elicited pro-inflammatory and fibrotic responses from PD patient peritoneal leukocytes, mesothelial cells and mouse peritoneal leukocytes. TLR2/4 blockade of human peritoneal cells or TLR2/4 knockouts inhibited these effects. PDS did not induce rapid ERK phosphorylation or IκB-α degradation, suggesting that they do not contain components capable of direct TLR activation. However, PDS increased the release of Hsp70 and hyaluronan, both TLR2/4 DAMP ligands, by human and mouse peritoneal cells, and their blockade decreased PDS-driven inflammation. Soluble TLR2, a TLR inhibitor, reduced PDS-induced pro-inflammatory and fibrotic cytokine release ex vivo. Daily catheter infusion of PDS in mice caused peritoneal fibrosis, but co-administration of soluble TLR2 prevented fibrosis, suppressed pro-fibrotic gene expression and pro-inflammatory cytokine production, reduced leukocyte/neutrophil recruitment, recovered Treg cell levels and increased the Treg:Th17 ratio. Thus, TLR2/4, Hsp70 and hyaluronan showed major roles in PDS-induced peritoneal inflammation and fibrosis. The study demonstrates the therapeutic potential of a TLR-DAMP targeting strategy to prevent PDS-induced fibrosis.

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

“…The role of TLR2 and TLR4 in sterile inflammatory and fibrotic responses of peritoneal cells resulting from exposure to PD solutions (PDS) was also evaluated ( Raby et al, 2018 ). A number of PDS elicited pro-inflammatory and pro-fibrotic responses (CXCL-8/IL-8, IL-6, TNF-α, TGF-β, and IL-1β) from PDE-isolated uremic peritoneal leukocytes and mesothelial cells (from greater omentum), including those glucose-based (1.36 and 2.27% glucose Dianeal ® , Physioneal ® , Stay Safe ® ) or icodextrin-based (Extraneal ® ), having low pH (Dianeal ® , Extraneal ® , Stay Safe ® ) or physiologic pH (Physioneal ® ).…”

“…Open circles outside the dotted lines correspond to genes modulated in a non-statistically significant manner. Adapted with permission from Raby et al (2018) .…”

“…The immune mechanisms linking infection-induced or sterile inflammation with the onset, development and regulation of PD-associated peritoneal fibrosis are poorly defined and thus the focus of intense investigation ( Fielding et al, 2014 ; Liappas et al, 2015 , 2016 ; Raby et al, 2018 ). Consequently, effective therapies to prevent PD-associated fibrosis remain to be developed.…”

“…Inappropriate TLR activation may result in serious inflammatory conditions, therefore, they are being considered as therapeutic targets for the prevention and/or treatment of a number of inflammatory pathologies ( Riedemann et al, 2003 ; Kanzler et al, 2007 ; Mollnes et al, 2008 ; Dunne et al, 2011 ; Raby et al, 2013 ). Given the close link between inflammation and fibrosis, and the recognized involvement of TLRs in tissue fibrosis ( Anders and Schaefer, 2014 ), we recently assessed the role that TLRs play in peritoneal fibrosis development during PD ( Raby et al, 2017 , 2018 ). Here, we review the findings and discuss the potential of reducing peritoneal TLR activity by using the soluble form of TLR2, a TLR modulator, as a therapeutic strategy to prevent PD-associated peritoneal fibrosis.…”

Protective effects and mechanisms of omega‐3 polyunsaturated fatty acid on intestinal injury and macrophage polarization in peritoneal dialysis rats

“…The fibrosis process and inflammation are often two cooperative parts which are frequently induced bidirectionally . Inflammatory cytokines induced by peritoneal dialysis solutions, such as glucose and glucose degradation products, can induce fibrosis . It is generally accepted that classically activated macrophages (M1) secrete many pro‐inflammatory cytokines which are involved in tissue damage, whereas alternatively activated macrophages (M2) secrete the growth factor beta (TGF‐β) which participates in tissue remodeling and fibrosis occurrence .…”