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TRIM33 Prevents Pulmonary Fibrosis by Impairing TGF-β1 Signaling
PDPI Surakarta, 20 Mar 2020 20:27:08


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.

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