Endogenous myeloperoxidase is a mediator of joint inflammation and damage in experimental arthritis

Dragana Odobasic, Yuan Yang, Ruth C.M. Muljadi, Kim M. O'Sullivan, Wenping Kao, Malcolm Smith, Eric F. Morand, Stephen R. Holdsworth

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Objective Myeloperoxidase (MPO) is implicated as a local mediator of tissue damage when released extracellularly in many chronic inflammatory diseases. The purpose of this study was to explore the role of endogenous MPO in experimental rheumatoid arthritis (RA). Methods K/BxN serum-transfer arthritis was induced in C57BL/6 wild-type (WT) and MPO knockout (MPO-/-) mice, and disease development was assessed. MPO activity was measured in joint tissues from mice with or without K/BxN arthritis. Collagen-induced arthritis (CIA) was induced in WT and MPO-/- mice, and disease development and immune responses were examined. MPO expression was assessed in synovial biopsy samples from patients with active RA, and the effect of MPO on synovial fibroblasts was tested in vitro. Results MPO was up-regulated in the joints of mice with K/BxN arthritis, and MPO deficiency attenuated the severity of the disease without affecting circulating cytokine levels. In CIA, MPO-/- mice had enhanced CD4+ T cell responses and reduced frequency of regulatory T cells in the lymph nodes and spleen, as well as augmented interleukin-17A and diminished interferon-γ secretion by collagen-stimulated splenocytes, without an effect on circulating anticollagen antibody levels. Despite enhanced adaptive immunity in secondary lymphoid organs, CIA development was attenuated in MPO-/- mice. Intracellular and extracellular MPO was detected in the synovium of patients with active RA, and human MPO enhanced the proliferation and decreased the apoptosis of synovial fibroblasts in vitro. Conclusion MPO contributes to the development of arthritis despite suppressing adaptive immunity in secondary lymphoid organs. This suggests distinct effects of local MPO on arthritogenic effector responses.

Original languageEnglish
Pages (from-to)907-917
Number of pages11
JournalArthritis and Rheumatology
Volume66
Issue number4
DOIs
Publication statusPublished - Apr 2014
Externally publishedYes

Keywords

  • chronic inflammatory diseases
  • rheumatoid arthritis
  • adaptive immunity

Fingerprint Dive into the research topics of 'Endogenous myeloperoxidase is a mediator of joint inflammation and damage in experimental arthritis'. Together they form a unique fingerprint.

  • Cite this

    Odobasic, D., Yang, Y., Muljadi, R. C. M., O'Sullivan, K. M., Kao, W., Smith, M., Morand, E. F., & Holdsworth, S. R. (2014). Endogenous myeloperoxidase is a mediator of joint inflammation and damage in experimental arthritis. Arthritis and Rheumatology, 66(4), 907-917. https://doi.org/10.1002/art.38299