TRIM33 prevents pulmonary fibrosis by impairing TGF-ß1 signalling.

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)-ß1 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-ß/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-ß1 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-ß1 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-ß1. 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.

Halo Sign and Eosinophilia: What Is Your Diagnosis?

Blood eosinophilia associated with transient and migrating nodules with a halo sign on chest computed tomography scan should suggest larva migrans related to toxocariasis or ascaris suum.