RATIONALE:Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterised by myofibroblast proliferation and abnormal extracellular matrix (ECM) accumulation in the lungs. Transforming-growth-factor (TGF)-β1 initiates key profibrotic signaling involving the SMADs pathway and the small heat shock protein αB-crystallin (HSPB5). TRIpartite Motif-containing 33 (TRIM33) has been reported to negatively regulate TGF-β/SMADs signaling but its role in fibrogenesis remains unknown. OBJECTIVES: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 hematopoietic-specific Trim33 knock-out (KO) 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. Hematopoietic-specific Trim33-KO sensitised mice to BLM-induced fibrosis. In primary lung fibroblasts and 3D-lung tissue slices, Trim33-deficiency increased TGF-β1-downstream gene expression. 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.