title: Toll-Like Receptors 2 and 4 Are Potential Therapeutic Targets in Peritoneal Dialysis-Associated Fibrosis.
abstract: Peritoneal dialysis (PD) remains limited by dialysis failure due to peritoneal membrane fibrosis driven by inflammation caused by infections or sterile cellular stress. Given the fundamental role of Toll-like receptors (TLRs) and complement in inflammation, we assessed the potential of peritoneal TLR2, TLR4 and C5a receptors, C5aR and C5L2, as therapeutic targets in PD-associated fibrosis. We detected TLR2-, TLR4-, and C5aR-mediated proinflammatory and fibrotic responses to bacteria that were consistent with the expression of these receptors in peritoneal macrophages (TLR2/4, C5aR) and mesothelial cells (TLR2, C5aR). Experiments in knockout mice revealed a major role for TLR2, a lesser role for TLR4, a supplementary role for C5aR, and no apparent activity of C5L2 in infection-induced peritoneal fibrosis. Similarly, antibody blockade of TLR2, TLR4, or C5aR differentially inhibited bacteria-induced profibrotic and inflammatory mediator production by peritoneal leukocytes isolated from the peritoneal dialysis effluent (PDE) of noninfected uremic patients. Additionally, antibodies against TLR2, TLR4, or the coreceptor CD14 reduced the profibrotic responses of uremic leukocytes to endogenous components present in the PDE of noninfected patients. Enhancing TLR2-mediated inflammation increased fibrosis in vivo Furthermore, soluble TLR2 (sTLR2), a negative modulator of TLRs that we detected in PDE, inhibited PDE-induced, TLR2- or TLR4-mediated profibrotic responses. Notably, sTLR2 treatment markedly reduced Gram-positive and -negative bacteria-induced fibrosis in vivo, inhibiting proinflammatory and fibrotic genes without affecting infection clearance. These findings reveal the influence of peritoneal TLR2 and TLR4 on PD-associated fibrosis and describe a therapeutic strategy against fibrosis.
authors.affiliation: Division of Infection and Immunity and The Wales Kidney Research Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom; RabyA@cardiff.ac.uk wmdmol@cardiff.ac.uk.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Raby
authors.affiliation: Division of Infection and Immunity and The Wales Kidney Research Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Chantal S
authors.initials: CS
authors.lastname: Colmont
authors.affiliation: Division of Infection and Immunity and The Wales Kidney Research Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Ann
authors.initials: A
authors.lastname: Kift-Morgan
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck, Lubeck, Germany; and.|Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, Ohio.
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.affiliation: Division of Infection and Immunity and The Wales Kidney Research Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eberl
authors.affiliation: Division of Infection and Immunity and The Wales Kidney Research Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Donald
authors.initials: D
authors.lastname: Fraser
authors.affiliation: Division of Infection and Immunity and The Wales Kidney Research Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Topley
authors.affiliation: Division of Infection and Immunity and The Wales Kidney Research Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom; RabyA@cardiff.ac.uk wmdmol@cardiff.ac.uk.
authors.forename: Mario O
authors.initials: MO
authors.lastname: Labéta
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D056627:Peritoneal Fibrosis / Q000188:drug therapy* / Q000209:etiology*; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
chemical_list: C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
keywords: clinical immunology; fibrosis; immunology and pathology; peritoneal dialysis