TY - JOUR T1 - TRIM33 prevents pulmonary fibrosis by impairing TGF-β1 signalling JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.01346-2019 VL - 55 IS - 6 SP - 1901346 AU - Pierre-Marie Boutanquoi AU - Olivier Burgy AU - Guillaume Beltramo AU - Pierre-Simon Bellaye AU - Lucile Dondaine AU - Guillaume Marcion AU - Lenny Pommerolle AU - Aurélie Vadel AU - Maximilien Spanjaard AU - Oleg Demidov AU - Arnaud Mailleux AU - Bruno Crestani AU - Martin Kolb AU - Carmen Garrido AU - Françoise Goirand AU - Philippe Bonniaud Y1 - 2020/06/01 UR - http://erj.ersjournals.com/content/55/6/1901346.abstract N2 - 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.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 ER -