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Caveolin-1 regulates leucocyte behaviour in fibrotic lung disease
  1. Elena Tourkina1,
  2. Mathieu Richard1,
  3. James Oates1,
  4. Ann Hofbauer1,
  5. Michael Bonner1,
  6. Pal Gööz1,
  7. Richard Visconti2,
  8. Jing Zhang2,
  9. Sergei Znoyko1,
  10. Corey M Hatfield1,
  11. Richard M Silver1,
  12. Stanley Hoffman1,2
  1. 1Division of Rheumatology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
  2. 2Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA
  1. Correspondence to Elena Tourkina, Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 912 MSC 637, Charleston, SC 29425, USA; tourkine{at}musc.edu

Abstract

Objectives Reduced caveolin-1 levels in lung fibroblasts from patients with scleroderma and the lungs of bleomycin-treated mice promote collagen overexpression and lung fibrosis. This study was undertaken to determine whether caveolin-1 is deficient in leucocytes from bleomycin-treated mice and patients with scleroderma and to examine the consequences of this deficiency and its reversal.

Methods Mice or cells received the caveolin-1 scaffolding domain (CSD) peptide to reverse the pathological effects of reduced caveolin-1 expression. In bleomycin-treated mice, the levels of caveolin-1 in leucocytes and the effect of CSD peptide on leucocyte accumulation in lung tissue were examined. To validate the results in human disease and to identify caveolin-1-regulated molecular mechanisms, monocytes and neutrophils were isolated from patients with scleroderma and control subjects and caveolin-1, extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, CXC chemokine receptor 4 (CXCR4) and matrix metalloproteinase 9 (MMP-9) expression/activation were evaluated. These parameters were also studied in monocytes treated with cytokines or CSD peptide.

Results Leucocyte caveolin-1 is important in lung fibrosis. In bleomycin-treated mice, caveolin-1 expression was diminished in monocytes and CSD peptide inhibited leucocyte recruitment into the lungs. These observations are relevant to human disease. Monocytes and neutrophils from patients with scleroderma contained less caveolin-1 and more activated ERK, JNK and p38 than those from control subjects. Treatment with CSD peptide reversed ERK, JNK and p38 hyperactivation. Scleroderma monocytes also overexpressed CXCR4 and MMP-9, which was inhibited by the CSD peptide. Cytokine treatment of normal monocytes caused adoption of the scleroderma phenotype (low caveolin-1, high CXCR4 and MMP-9 and signalling molecule hyperactivation).

Conclusions Caveolin-1 downregulation in leucocytes contributes to fibrotic lung disease, highlighting caveolin-1 as a promising therapeutic target in scleroderma.

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Footnotes

  • Funding This work was supported by the following grants: Scleroderma Foundation (to ET), NIH NIAMS grant K01 AR054143 (to ET), NIH NIAMS grant R03 AR 056767 (to ET), NIH NHLBI grant R01 HL73718 (to SH), NIH NIAMS grant P60 AR049459 (Multidisciplinary Clinical Research Center to RMS) and NIH NCRR Construction Grant C06 RR015455.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Medical University of South Carolina Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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