The Inflammatory Transcription Factor C/EBPβ Plays a Critical Role in Cardiac Fibroblast Differentiation and a Rat Model of Cardiac Fibrosis Induced by Autoimmune Myocarditis

Abstract

The aim of the present study was to investigate the mechanisms of CCAAT/enhancer-binding protein β (C/ EBPβ) in cardiac myofibroblast (CMF) differentiation and in a rat model of cardiac fibrosis induced by experimental autoimmune myocarditis (EAM). In vitro studies performed in primary neonatal rat CMF revealed that silencing of C/EBPβ expression (via lentiviral mediated shRNA strategies) was sufficient to reduce C/EBPβ mRNA and protein levels as well as to decrease the expressions of actin cytoskeletal proteins, cofilin, and filamin A (FLNA). TGFβ increased IL-1β, IL-6 and TNF-a production in cardiac fibroblasts (CF), while C/EBPβ knockdown reduced the secretion of these inflammatory mediators. In vivo studies performed in rats exhibiting EAM revealed that lentiviralmediated silencing of C/EBPβ was sufficient to reduce the expression of C/EBPβ as well as inflammation and fibrosis in the hearts of EAM rats, when compared to controls. Echocardiography further revealed that C/EBPβ knockdown was sufficient to significantly improve cardiac dimensions and function in EAM rats. Immunohistochemical results showed that C/EBPβ knockdown attenuated the expression of C/EBPβ protein as well as the expressions of collagen I, collagen III, MMP-2, MMP-9, and α-SMA in heart tissue sections from rats in the EAM + Lenti-shC/EBPβ group. Strategies targeted at inhibiting C/EBPβ expression can be potentially exploited to regulate cofilin and FLNA expression, thereby regulating actin polymerization/depolymerization, cytoskeleton rearrangement, and CF differentiation into CMF and the production of inflammatory cytokines. C/EBPβ knock down reduces the degree of inflammation-mediated myocardial fibrosis in a rat model of EAM.

Cofilin‐1 participates in the hyperfunction of myeloid dendritic cells in patients with severe aplastic anaemia

“…Thus, the cytoskeleton undergoes intense remodelling during this process. The role of the cytoskeletal system, including cofilin, fascin, profilin 1 and other cytoskeletal binding proteins, in autoimmune diseases has been reported 9,10 . In our previous study, we found that the expression of profilin 1 increases on the mDCs of patients with SAA, and this may affect mDC function 17 .…”

“…The role of the cytoskeletal system, including cofilin, fascin, profilin 1 and other cytoskeletal binding proteins, in autoimmune diseases has been reported. 9 , 10 In our previous study, we found that the expression of profilin 1 increases on the mDCs of patients with SAA, and this may affect mDC function. 17 In the present study, we observed that the expression of cofilin‐1 in mDCs from patients with SAA increased at both mRNA and protein levels.…”

“…On the other hand, it can generate new free ends and provide more actin monomer sources for the extension of the fast‐growing end of F‐actin to increase actin polymerization 7,8 . Previous studies have elucidated the role of the cytoskeletal system in autoimmune diseases, including cofilin‐1 9,10 . Actin polymerization and depolymerization, mediated by cofilin‐1, generate a time‐space‐coordinated dynamic actin cycle that is critical to various biological processes, including the immune response.…”

“… 7 , 8 Previous studies have elucidated the role of the cytoskeletal system in autoimmune diseases, including cofilin‐1. 9 , 10 Actin polymerization and depolymerization, mediated by cofilin‐1, generate a time‐space‐coordinated dynamic actin cycle that is critical to various biological processes, including the immune response. It has been confirmed that cofilin‐1 plays an important role in the function of DCs.…”

CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding

“…For instance, protein levels of C/EBP α decrease in carbon tetrachloride- (CCl 4 -) induced fibrotic liver tissue, and overexpression of C/EBP α in the liver can alleviate CCl 4 -induced hepatic fibrosis [ 28 , 37 ]. C/EBP β expression is inhibited in diabetic cardiomyopathy- (DCM-) induced fibrotic heart tissue, and overexpression of C/EBP β inhibits this cardiac fibrosis, while C/EBP β knockdown attenuates heart fibrotic pathology in rat models of experimental autoimmune myocarditis (EAM) [ 34 , 38 ]. The overactivation of C/EBP γ induced by IL-1 β inhibits IL-6 expression in lung epithelial cells, which indirectly suppresses lung fibrosis [ 25 , 39 ].…”