TRIM33 regulates TGF-ß1 secretion and Epithelial-Mesenchymal Transition in pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by extracellular-matrix (ECM) accumulation in the lungs. Transforming-growth-factor (TGF)-s1 is a key profibrotic growth factor involving Smad pathway. Tripartite motif containing 33 (TRIM33) has previously been reported to exert a negative control on Smad signaling but its role in fibrogenesis remains unknown. Methods: TRIM33 expression was assessed in IPF. Bleomycin (BLM) or NaCl were injected in conditional hematopoietic-specific TRIM33 knock-out mice. In vitro, Bone Marrow-derived Macrophage (BMDM) and primary lung fibroblasts were depleted for TRIM33 and treated with TGF-s1. In vitro we characterized the relationship between TRIM33 and HSPB5. Results: TRIM33 was overexpressed in the lung of IPF patients compared to controls. Similar results were observed in fibrososis rodent model. Interestingly, TRIM33 inhibition in BMDM led to a 3-fold increase of TGF-s1 secretion (ELISA) upon BLM treatment. We therefore used conditional hematopoietic-specific TRIM33 knock-out mice and demonstrated that these mice were more sensitive to BLM compared to WT mice with 1) a significant increase in collagen deposition (Sircol assay), 2) an increase in EMT marker mRNA expression 3) a significant increase (X2) of TGF-s1 level in BALF. TRIM33 deficient lung fibroblasts were more sensitive to TGF-s1 treatment with a significantly increased mRNA expression of EMT marker. In vitro, we demonstrated that HSPB5 was able 1) to bind to TRIM33 (BLI) 2) to impair with TRIM33 activity. Conclusion: Our results demonstrate a key role of TRIM33 in lung fibrosis. Inhibitors of TRIM33 and HSPB5 may be of interest for the treatment of IPF