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The cathelicidins LL-37 and rCRAMP are associated with pathogenic events of arthritis in humans and rats
  1. Markus H Hoffmann1,
  2. Heiko Bruns2,
  3. Liselotte Bäckdahl1,
  4. Petra Neregård3,
  5. Birgit Niederreiter4,
  6. Martin Herrmann5,
  7. Anca Irinel Catrina3,
  8. Birgitta Agerberth6,
  9. Rikard Holmdahl1
  1. 1Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
  2. 2Department of Internal Medicine 5, University of Erlangen-Nuremberg, Erlangen, Germany
  3. 3Rheumatology Unit, Department of Medicine at the Karolinska University Hospital Solna, Sweden
  4. 4Division of Rheumatology, Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria
  5. 5Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany
  6. 6Division of Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
  1. Correspondence to Dr Markus H Hoffmann, Department of Internal Medicine 3, University of Erlangen-Nuremberg, Glückstrasse 4a, 91054 Erlangen, Germany; markus.hoffmann{at}uk-erlangen.de

Abstract

Background In rheumatoid arthritis (RA), neutrophil granulocytes fuel inflammation and damage tissue in the joint by releasing cytotoxic agents, antimicrobial peptides, proteases and other inflammatory mediators. The human cathelicidin LL-37 has recently been implicated in the development of systemic lupus erythematosus and psoriasis.

Objective To elucidate if antimicrobial peptides (AMPs) contribute to the pathogenesis of arthritis.

Methods Expression of LL-37 was determined in synovial membranes from patients with arthritis and control subjects. Expression of the rat cathelicidin rCRAMP and defensins was characterised in joints, blood and secondary lymphoid organs during pristane-induced arthritis (PIA) in rats and in a transfer model of PIA induced by CD4 T cells. Serum samples of rats with arthritis were tested for IgG and IgM autoantibodies against rCRAMP by immunoblot and for interferon (IFNα) by ELISA.

Results Cathelicidins are strongly upregulated in RA synovial membranes and in joints from rats with arthritis as compared with healthy joints. Expression was most prominent in neutrophil granulocytes and macrophages/osteoclasts. Cathelicidin expression is also upregulated in the blood and spleen of pristane-injected rats, with strongest expression detected in activated CD62L− cells coexpressing granulocyte and monocyte markers. Pristane injection caused accumulation of low-density granulocytes in the blood. After pristane injection, the increased expression of rCRAMP coincided with higher levels of cell death, raised levels of interferon (IFN)α and development of autoantibodies.

Conclusions Our results show strong upregulation of cathelicidins and β-defensins coinciding with pathological events of arthritis. Higher expression and release of AMPs might contribute to development and/or maintenance of disease by systemic or local mechanisms.

  • Autoimmunity
  • Rheumatoid Arthritis
  • Autoantibodies

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