[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Boutanquoi, Pierre-Marie; INSERM U1231, Faculty of Medicine and Pharmacy, University of Bourgogne-Franche
Burgy, Olivier; INSERM U1231, Faculty of Medicine and Pharmacy, University of Bourgogne-Franche ; Division of Pulmonary Sciences and Critical Care Medicine, Dept of Medicine,
Beltramo, Guillaume; INSERM U1231, Faculty of Medicine and Pharmacy, University of Bourgogne-Franche ; Dept of Pulmonary Medicine and Intensive Care Unit, University Hospital, ; Reference Center for Rare Lung Diseases, University Hospital, Bourgogne-Franche
Bellaye, Pierre-Simon; Cancer Center Georges François Leclerc, Dijon, France.
Dondaine, Lucile; INSERM U1231, Faculty of Medicine and Pharmacy, University of Bourgogne-Franche ; Reference Center for Rare Lung Diseases, University Hospital, Bourgogne-Franche
Marcion, Guillaume ; Université de Liège - ULiège > GIGA > GIGA I3 - Hematology ; INSERM U1231, Faculty of Medicine and Pharmacy, University of Bourgogne-Franche
Pommerolle, Lenny; INSERM U1231, Faculty of Medicine and Pharmacy, University of Bourgogne-Franche
Vadel, Aurélie; INSERM U1152, Faculty of Medicine, University of Bichat, Paris, France.
Spanjaard, Maximilien; INSERM U1231, Faculty of Medicine and Pharmacy, University of Bourgogne-Franche ; Dept of Pulmonary Medicine and Intensive Care Unit, University Hospital,
Demidov, Oleg ; INSERM U1231, Faculty of Medicine and Pharmacy, University of Bourgogne-Franche
Mailleux, Arnaud ; INSERM U1152, Faculty of Medicine, University of Bichat, Paris, France.
Crestani, Bruno; INSERM U1152, Faculty of Medicine, University of Bichat, Paris, France.
Kolb, Martin ; McMaster University, Hamilton, ON, Canada.
Garrido, Carmen; INSERM U1231, Faculty of Medicine and Pharmacy, University of Bourgogne-Franche
Goirand, Françoise; INSERM U1231, Faculty of Medicine and Pharmacy, University of Bourgogne-Franche ; These authors codirected this work and contributed equally to this work.
Bonniaud, Philippe; INSERM U1231, Faculty of Medicine and Pharmacy, University of Bourgogne-Franche ; Dept of Pulmonary Medicine and Intensive Care Unit, University Hospital, ; Reference Center for Rare Lung Diseases, University Hospital, Bourgogne-Franche ; These authors codirected this work and contributed equally to this work.
Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med 2015; 192: e3-e19.
Martinez FJ, Collard HR, Pardo A, et al. Idiopathic pulmonary fibrosis. Nat Rev Dis Primers 2017; 3: 17074.
Bonniaud P, Margetts PJ, Kolb M, et al. Adenoviral gene transfer of connective tissue growth factor in the lung induces transient fibrosis. Am J Respir Crit Care Med 2003; 168: 770-778.
Bonniaud P, Margetts PJ, Ask K, et al. TGF-β and Smad3 signaling link inflammation to chronic fibrogenesis. J Immunol 2005; 175: 5390-5395.
Bellaye PS, Wettstein G, Burgy O, et al. The small heat-shock protein αB-crystallin is essential for the nuclear localization of Smad4: impact on pulmonary fibrosis. J Pathol 2014; 232: 458-472.
Dupont S, Mamidi A, Cordenonsi M, et al. FAM/USP9x, a deubiquitinating enzyme essential for TGFβ signaling, controls Smad4 monoubiquitination. Cell 2009; 136: 123-135.
Morsut L, Yan KP, Enzo E, et al. Negative control of Smad activity by ectodermin/Tif1γ patterns the mammalian embryo. Development 2010; 137: 2571-2578.
Quéré R, Saint-Paul L, Carmignac V, et al. Tif1γ regulates the TGF-β1 receptor and promotes physiological aging of hematopoietic stem cells. Proc Natl Acad Sci USA 2014; 111: 10592-10597.
Gallouet AS, Ferri F, Petit V, et al. Macrophage production and activation are dependent on TRIM33. Oncotarget 2017; 8: 5111-5122.
Ferri F, Parcelier A, Petit V, et al. TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation. Nat Commun 2015; 6: 8900.
Hozumi H, Enomoto N, Kono M, et al. Prognostic significance of anti-aminoacyl-tRNA synthetase antibodies in polymyositis/dermatomyositis-associated interstitial lung disease: a retrospective case control study. PLoS One 2015; 10: e0120313.
Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183: 788-824.
Cecchini MJ, Hosein K, Howlett CJ, et al. Comprehensive gene expression profiling identifies distinct and overlapping transcriptional profiles in non-specific interstitial pneumonia and idiopathic pulmonary fibrosis. Respir Res 2018; 19: 153.
Shi Y, Gochuico BR, Yu G, et al. Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-β receptor I internalization and inhibiting transforming growth factor-β1 signaling. Am J Respir Crit Care Med 2013; 188: 831-841.
Chrétien ML, Legouge C, Martin RZ, et al. Trim33/Tif1γ is involved in late stages of granulomonopoiesis in mice. Exp Hematol 2016; 44: 727-739.
Decologne N, Wettstein G, Kolb M, et al. Bleomycin induces pleural and subpleural fibrosis in the presence of carbon particles. Eur Respir J 2010; 35: 176-185.
Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor β in human disease. N Engl J Med 2000; 342: 1350-1358.
Decologne N, Kolb M, Margetts PJ, et al. TGF-β1 induces progressive pleural scarring and subpleural fibrosis. J. Immunol 2007; 179: 6043-6051.
Uhl FE, Vierkotten S, Wagner DE, et al. Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures. Eur Respir J 2015; 46: 1150-1166.
Strieter RM. Con: Inflammatory mechanisms are not a minor component of the pathogenesis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2002; 165: 1206-1207.
Schiller HB, Mayr CH, Leuschner G, et al. Deep proteome profiling reveals common prevalence of MZB1-positive plasma B cells in human lung and skin fibrosis. Am J Respir Crit Care Med 2017; 196: 1298-1310.
Misharin AV, Morales-Nebreda L, Reyfman PA, et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med 2017; 214: 2387-2404.
Song E, Ouyang N, Hörbelt M, et al. Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts. Cell Immunol 2000; 204: 19-28.
Della Latta V, Cecchettini A, Del Ry S, et al. Bleomycin in the setting of lung fibrosis induction: from biological mechanisms to counteractions. Pharmacol Res 2015; 97: 122-130.
Bonner JC, Osornio-Vargas AR, Badgett A, et al. Differential proliferation of rat lung fibroblasts induced by the platelet-derived growth factor-AA, -AB, and -BB isoforms secreted by rat alveolar macrophages. Am J Respir Cell Mol Biol 1991; 5: 539-547.
Tanaka S, Jiang Y, Martinez GJ, et al. Trim33 mediates the proinflammatory function of Th17 cells. J Exp Med 2018; 215: 1853-1868.
Xie T, Wang Y, Deng N, et al. Single-cell deconvolution of fibroblast heterogeneity in mouse pulmonary fibrosis. Cell Rep 2018; 22: 3625-3640.
Wang L, Yang H, Lei Z, et al. Repression of Tif1γ by SOX2 promotes TGF-β-induced epithelial-mesenchymal transition in non-small-cell lung cancer. Oncogene 2016; 35: 867-877.
Ikeuchi Y, Dadakhujaev S, Chandhoke AS, et al. Tif1γ protein regulates epithelial-mesenchymal transition by operating as a small ubiquitin-like modifier (SUMO) E3 ligase for the transcriptional regulator SnoN1. J Biol Chem 2014; 289: 25067-25078.
Jingushi K, Ueda Y, Kitae K, et al. miR-629 targets TRIM33 to promote TGFβ/Smad signaling and metastatic phenotypes in ccRCC. Mol Cancer Res 2015; 13: 565-574.
Mugii N, Hasegawa M, Matsushita T, et al. Oropharyngeal dysphagia in dermatomyositis: associations with clinical and laboratory features including autoantibodies. PLoS One 2016; 11: e0154746.
