Article Text

PDF
Toll-like receptor 4 induced FcγR expression potentiates early onset of joint inflammation and cartilage destruction during immune complex arthritis: Toll-like receptor 4 largely regulates FcγR expression by interleukin 10
  1. P L E M van Lent,
  2. A B Blom,
  3. L Grevers,
  4. A Sloetjes,
  5. W B van den Berg
  1. Department of Rheumatology and Advanced Therapeutics, Radboud University Medical Centre, Nijmegen, The Netherlands
  1. Correspondence to:
    Dr P L E M van Lent
    Department of Rheumatology and Advanced Therapeutics, Geert Grooteplein 26-28, 6500 HB Nijmegen, The Netherlands; p.vanlent{at}reuma.umcn.nl

Abstract

Objective: To study the role of Toll-like receptor (TLR)2 and 4 in the onset of joint inflammation and cartilage destruction during immune complex-mediated arthritis (ICA), and its relationship with FcγR expression.

Materials and methods: ICA was induced in knee joints of TLR2−/− and TLR4−/− mice and their wild-type controls. Joint inflammation and cartilage destruction were measured in the knee joint using histology. mRNA levels were determined in synovial specimens and macrophages using quantitative polymerase chain reaction and cytokine protein levels in synovial washouts using Bioplex.

Results: Joint inflammation and cartilage destruction were not different in arthritic TLR2−/− and wild-type mice. By contrast, at day 1 after ICA induction, joint swelling and proteoglycan depletion in knee joints of TLR4−/− mice were considerably lower (inflammation 68–79% and proteoglycan depletion 27–76%) when compared with wild-type controls. Cytokine production at this time point was markedly reduced in TLR4−/− mice (interleukin (IL)1, IL6, macrophage inflammatory chemokine (MIP)-1α and keratinocyte-derived chemokine 49%, 72%, 68% and 84%, respectively). In arthritic synovia of TLR4−/− mice, and also after injection of the antigen poly-l-lysine (PLL) lysozyme alone, mRNA levels of FcγR, and the FcγR regulating cytokine IL10 were considerably lower. Stimulation of peritoneal macrophages with PLL lysozyme up regulated mRNA levels of FcγR and IL10, whereas neutralisation by anti-IL10 antibodies largely blocked FcγR up regulation. At day 4, joint inflammation and cartilage destruction were comparable in TLR4−/− mice and wild-type controls.

Conclusion: TLR4 regulates early onset of joint inflammation and cartilage destruction during ICA arthritis by up regulation of FcγR expression and enhanced cytokine production. TLR4-mediated up regulation of FcγR is largely mediated by IL10.

  • FcγR, Fcγ receptors
  • GAPDH, glyceraldehyde 3-phosphate dehydrogenase
  • ICA, immune complex-mediated arthritis
  • IFN, interferon
  • LPS, lipopolysaccharides
  • MIP, macrophage inflammatory chemokine
  • MMP, matrix metalloproteinase
  • PLL, poly-l-lysine
  • TLR, Toll-like receptor

Statistics from Altmetric.com

Footnotes

  • Published Online First 20 October 2006

  • Funding: This work was supported by the Dutch Arthritis Association.

  • Competing interests: None declared.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.