Abstract
Background Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterised by myofibroblast proliferation and abnormal extracellular matrix accumulation in the lungs. Transforming growth factor (TGF)-β1 initiates key profibrotic signalling involving the SMAD pathway and the small heat shock protein B5 (HSPB5). Tripartite motif-containing 33 (TRIM33) has been reported to negatively regulate TGF-β/SMAD signalling, but its role in fibrogenesis remains unknown. The objective of this study was to elucidate the role of TRIM33 in IPF.
Methods TRIM33 expression was assessed in the lungs of IPF patients and rodent fibrosis models. Bone marrow-derived macrophages (BMDM), primary lung fibroblasts and 3D lung tissue slices were isolated from Trim33-floxed mice and cultured with TGF-β1 or bleomycin (BLM). Trim33 expression was then suppressed by adenovirus Cre recombinase (AdCre). Pulmonary fibrosis was evaluated in haematopoietic-specific Trim33 knockout mice and in Trim33-floxed mice that received AdCre and BLM intratracheally.
Results TRIM33 was overexpressed in alveolar macrophages and fibroblasts in IPF patients and rodent fibrotic lungs. Trim33 inhibition in BMDM increased TGF-β1 secretion upon BLM treatment. Haematopoietic-specific Trim33 knockout sensitised mice to BLM-induced fibrosis. In primary lung fibroblasts and 3D lung tissue slices, Trim33 deficiency increased expression of genes downstream of TGF-β1. In mice, AdCre-Trim33 inhibition worsened BLM-induced fibrosis. In vitro, HSPB5 was able to bind directly to TRIM33, thereby diminishing its protein level and TRIM33/SMAD4 interaction.
Conclusion Our results demonstrate a key role of TRIM33 as a negative regulator of lung fibrosis. Since TRIM33 directly associates with HSPB5, which impairs its activity, inhibitors of TRIM33/HSPB5 interaction may be of interest in the treatment of IPF.
Abstract
TRIM33 has a protective role against fibrogenesis, inhibiting the TGF-β1 pathway through a direct association with HSPB5. Interactions between TRIM33, SMAD4 and HSPB5 may represent key targets to prevent the progression of pulmonary fibrosis. http://bit.ly/3aVCuxc
Footnotes
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Author contributions: P-M. Boutanquoi, F. Goirand and P. Bonniaud designed the study. P-M. Boutanquoi, O. Burgy, G. Beltramo, P-S. Bellaye, L. Dondaine, G. Marcion, L. Pommerolle, A. Vadel, M. Spanjaard and A. Mailleux performed the experiments and data analyses. O. Demidov supervised the mouse breeding. M. Kolb provided adenoviruses. P-M. Boutanquoi prepared the manuscript. B. Crestani, M. Kolb and C. Garrido brought important intellectual content. O. Burgy, P-S. Bellaye, F. Goirand and P. Bonniaud provided critical revision of the manuscript. All authors have read, reviewed and approved the final submitted manuscript and agree to take public responsibility for it.
Conflict of interest: P-M. Boutanquoi has nothing to disclose.
Conflict of interest: O. Burgy has nothing to disclose.
Conflict of interest: G. Beltramo has nothing to disclose.
Conflict of interest: P-S. Bellaye has nothing to disclose.
Conflict of interest: L. Dondaine has nothing to disclose.
Conflict of interest: G. Marcion has nothing to disclose.
Conflict of interest: L. Pommerolle has nothing to disclose.
Conflict of interest: A. Vadel has nothing to disclose.
Conflict of interest: M. Spanjaard has nothing to disclose.
Conflict of interest: O. Demidov has nothing to disclose.
Conflict of interest: A. Mailleux has nothing to disclose.
Conflict of interest: B. Crestani reports personal fees for lectures and travel support for meeting attendance from AstraZeneca, grants, personal fees for lectures and travel support for meeting attendance from Boehringer Ingelheim and Roche, grants from MedImmune, personal fees for lectures and consultancy, and travel support for meeting attendance from Sanofi, personal fees for advisory board work from Genzyme, outside the submitted work.
Conflict of interest: M. Kolb reports grants and personal fees from Roche, Boehringer Ingelheim and Prometic, grants from GSK, Respivert, Alkermes, Pharmaxis and Canadian Institute for Health Research, personal fees from Genoa, Indalo, Third Pole and Pieris, outside the submitted work.
Conflict of interest: C. Garrido has nothing to disclose.
Conflict of interest: F. Goirand has nothing to disclose.
Conflict of interest: P. Bonniaud reports personal fees for advisory board work and travel support for meeting attendance from Roche and Novartis, personal fees for advisory board work and reimbursement of meeting registration from Boehringer, personal fees for advisory board work from TEVA and AstraZeneca, travel support for meeting attendance from Chiesi, reimbursement of meeting registration from Stallergene, outside the submitted work.
Support statement: This work received funding from the Agence Nationale de la Recherche (ANR-16-CE14-0004-01 SHOT-IPF). P-M. Boutanquoi is supported by the “Fonds de Recherche en Santé Respiratoire” Appel d'offres Formation par la Recherche 2018/Société de Pneumologie de Langue Française (SPLF). O. Burgy is supported by the French “Investissements d'Avenir” programme, project ISITE-BFC (contract ANR-15-IDEX-0003). The C. Garrido team has the “label d'excellence” from La Ligue National Contre le Cancer and L'Association pour la “Recherche sur le Cancer” and belongs to the LabEx LipSTIC and GR-Ex. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received July 8, 2019.
- Accepted March 2, 2020.
- Copyright ©ERS 2020