Acute Liver Injury after CCl4 Administration Is Independent of Smad7 Expression in Myeloid Cells

Published on Nov 6, 2019in International Journal of Molecular Sciences4.556
· DOI :10.3390/IJMS20225528
Jessica Endig2
Estimated H-index: 2
(UHH: University of Hamburg),
Ludmilla Unrau3
Estimated H-index: 3
(UHH: University of Hamburg)
+ 6 AuthorsLinda Diehl23
Estimated H-index: 23
(UHH: University of Hamburg)
Myeloid cells are essential for the initiation and termination of innate and adaptive immunity that create homeostasis in the liver. Smad7 is an inhibitor of the transforming growth factor β (TGF-β) signaling pathway, which regulates inflammatory cellular processes. Knockdown of Smad7 in hepatocytes has been shown to promote liver fibrosis, but little is known about the effects of Smad7 in myeloid cells during inflammatory responses in the liver. Using mice with a myeloid-specific knockdown of Smad7 (LysM-Cre Smad7fl/fl), we investigated the impact of Smad7 deficiency in myeloid cells on liver inflammation and regeneration using the well-established model of CCl4-mediated liver injury. Early (24/48 h) and late (7 d) time points were analyzed. We found that CCl4 induces severe liver injury, with elevated serum ALT levels, centrilobular and periportal necrosis, infiltrating myeloid cells and an increase of inflammatory cytokines in the liver. Furthermore, as expected, inflammation peaked at 24 h and subsided after 7 d. However, the knockdown of Smad7 in myeloid cells did not affect any of the investigated parameters in the CCl4-treated animals. In summary, our results suggest that the inhibition of TGF-β signaling via Smad7 expression in myeloid cells is dispensable for the induction and control of acute CCl4-induced liver injury.
📖 Papers frequently viewed together
20132.74PLOS ONE
8 Authors (Guan-Xian Liu, ..., Hui-Yao Lan)
69 Citations
20122.74PLOS ONE
8 Authors (Li-xia Tang, ..., Hui Y. Lan)
83 Citations
94 Citations
#1Edoardo Troncone (University of Rome Tor Vergata)H-Index: 8
#2Irene Marafini (University of Rome Tor Vergata)H-Index: 21
Last. Giovanni Monteleone (University of Rome Tor Vergata)H-Index: 77
view all 4 authors...
In physiological conditions, the activity of the intestinal immune system is tightly regulated to prevent tissue-damaging reactions directed against components of the luminal flora. Various factors contribute to maintain immune homeostasis and diminished production and/or function of such molecules trigger and/or propagate detrimental signals, which can eventually lead to chronic colitis and colon cancer. One such a molecule is transforming growth factor-1 (TGF-1), a cytokine produced by many ...
39 CitationsSource
#1Markus F. Neurath (FAU: University of Erlangen-Nuremberg)H-Index: 134
The management of IBD has undergone major advances with the development of biologic agents. Here, Markus Neurath provides an overview of current and future therapeutic targets for IBD, including insights into the mechanisms and rationale behind such approaches.
253 CitationsSource
#1Yun Zhang (Duke University)H-Index: 6
#2Peter B. Alexander (Duke University)H-Index: 14
Last. Xiao-Fan Wang (Duke University)H-Index: 81
view all 3 authors...
: The transforming growth factor β (TGF-β) family controls many fundamental aspects of cellular behavior. With advances in the molecular details of the TGF-β signaling cascade and its cross talk with other signaling pathways, we now have a more coherent understanding of the cytostatic program induced by TGF-β. However, the molecular mechanisms are still largely elusive for other cellular processes that are regulated by TGF-β and determine a cell's proliferation and survival, apoptosis, dormancy,...
130 CitationsSource
#1Silvia Sedda (University of Rome Tor Vergata)H-Index: 13
#2Veronica De Simone (University of Rome Tor Vergata)H-Index: 7
Last. Giovanni Monteleone (University of Rome Tor Vergata)H-Index: 77
view all 14 authors...
Refractory coeliac disease (RCD) is a form of coeliac disease (CD) resistant to gluten-free diet and associated with elevated risk of complications. Many effector cytokines over-produced in the gut of patients with RCD are supposed to amplify the tissue-destructive immune response, but it remains unclear if the RCD-associated mucosal inflammation is sustained by defects in counter-regulatory mechanisms. The aim of the present study was to determine whether RCD-related inflammation is marked by h...
10 CitationsSource
#1Teng Feng (Heidelberg University)H-Index: 6
#2J Dzieran (Heidelberg University)H-Index: 10
Last. NM Meindl-Beinker (Heidelberg University)H-Index: 10
view all 16 authors...
TGF-β signaling in liver cells has variant roles in the dynamics of liver diseases, including hepatocellular carcinoma (HCC). We previously found a correlation of high levels of the important endogenous negative TGF-β signaling regulator SMAD7 with better clinical outcome in HCC patients. However, the underlying tumor-suppressive molecular mechanisms are still unclear. Here, we show that conditional (TTR-Cre) hepatocyte-specific SMAD7 knockout (KO) mice develop more tumors than wild-type and cor...
12 CitationsSource
#1Isabel Fabregat (University of Barcelona)H-Index: 62
Last. Peter ten DijkeH-Index: 13
view all 7 authors...
The transforming growth factor-beta (TGF-β) family signalling pathways play essential roles in the regulation of different cellular processes, including proliferation, differentiation, migration or cell death, which are essential for the homeostasis of tissues and organs. Because of the diverse and pleiotropic TGF-β functions, deregulation of its pathways contributes to human disease. In the case of the liver, TGF-β signalling participates in all stages of disease progression, from initial liver...
241 CitationsSource
#1Krishnan MohanKumar (USF: University of South Florida)H-Index: 12
#2Kopperuncholan Namachivayam (USF: University of South Florida)H-Index: 10
Last. Akhil MaheshwariH-Index: 33
view all 7 authors...
Smad7 interrupts TGF-β signaling in intestinal macrophages and promotes inflammatory activation of these cells during necrotizing enterocolitis
31 CitationsSource
#1Sofia Karkampouna (LUMC: Leiden University Medical Center)H-Index: 10
#2Marie-José Goumans (LUMC: Leiden University Medical Center)H-Index: 76
Last. Marianna Kruithof-de Julio (LUMC: Leiden University Medical Center)H-Index: 16
view all 5 authors...
Liver exhibits a remarkable maintenance of functional homeostasis in the presence of a variety of damaging toxic factors. Tissue regeneration involves cell replenishment and extracellular matrix remodeling. Key regulator of homeostasis is the transforming growth factor-β (TGFβ) cytokine. To understand the role of TGFβ during liver regeneration, we used the single-dose carbon tetrachloride (CCl4) treatment in mice as a model of acute liver damage. We combined this with in vivo inhibition of the T...
26 CitationsSource
#1Christian Liedtke (RWTH Aachen University)H-Index: 34
#2Tom Luedde (RWTH Aachen University)H-Index: 64
Last. Ralf Weiskirchen (RWTH Aachen University)H-Index: 75
view all 10 authors...
Liver fibrosis is defined as excessive extracellular matrix deposition and is based on complex interactions between matrix-producing hepatic stellate cells and an abundance of liver-resident and infiltrating cells. Investigation of these processes requires in vitro and in vivo experimental work in animals. However, the use of animals in translational research will be increasingly challenged, at least in countries of the European Union, because of the adoption of new animal welfare rules in 2013....
215 CitationsSource
#1Juan E. Puche (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 3
#2Youngmin A. Lee (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 17
Last. Scott L. Friedman (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 142
view all 10 authors...
Hepatic stellate cells (HSCs) are well-characterized non-parenchymal cells of the liver with established roles in fibrosis, repair and immunity (1). During liver injury, quiescent HSCs undergo activation, secreting a repertoire of molecules involved in cell proliferation, chemotaxis, inflammation and fibrosis, among others. Although their role in fibrogenesis is well established, the contributions of HSCs to acute hepatocellular damage and tissue homeostasis are not well understood. Models to ma...
92 CitationsSource
Cited By5
#1Hung-Jen ShihH-Index: 2
#2Chao-Yuan Chang (TMU: Taipei Medical University)H-Index: 2
Last. Chun Jen HuangH-Index: 16
view all 6 authors...
Three major cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, mediate endotoxemia-induced liver injury. With the similar structures to the binding domains of the three cytokines to their cognate receptors, the novel peptide KCF18 can simultaneously inhibit TNF-α, IL-1β, and IL-6. We elucidated whether KCF18 can alleviate injury of liver in endotoxemic mice. Adult male mice (BALB/cJ) were intraperitoneally (i.p.) administered lipopolysaccharide (LPS, 15 mg/kg...
#1Dan Li (CQMU: Chongqing Medical University)
#2E Yang (CQMU: Chongqing Medical University)H-Index: 1
Last. Heng-shu Zhang (CQMU: Chongqing Medical University)H-Index: 1
view all 4 authors...
To explore the relationship between methylated binding protein 2 (MeCP2) and mothers against decapentaplegic homolog 7 (Smad7) in the pathogenesis and development of pathological scars. Immunohistochemistry, Western blot and real-time polymerase chain reaction (RT-PCR) were used to detect the expression of MeCP2 in different types of human scars and hypertrophic scars at different growth times. The methylation status of Smad7 gene promoter in different scar tissues was determined by methylation-...
#1Igor Y. Iskusnykh (UTHSC: University of Tennessee Health Science Center)H-Index: 5
#2E. D. Kryl’skii (Voronezh State University)H-Index: 2
Last. Nikolai Fattakhov (UM: University of Miami)
view all 12 authors...
Inflammation and an increase in antioxidant responses mediated by oxidative stress play an important role in the pathogenesis of acute liver injury (ALI). We utilized in silico prediction of biological activity spectra for substances (PASS) analysis to estimate the potential biological activity profile of deethylated ethoxyquin (DEQ) and hypothesized that DEQ exhibits antioxidant and anti-inflammatory effects in a rat model of carbon tetrachloride (CCl4)-induced ALI. Our results demonstrate that...
#1Kun Li (Zhengzhou University)H-Index: 5
#2Mingzhe Cui (Zhengzhou University)H-Index: 1
Last. Shuiting Zhai (Zhengzhou University)H-Index: 3
view all 5 authors...
Abstract Objective Extracellular vesicles (EVs) are vital mediators of transferring microRNAs (miRNAs). We focused on effect of miR-185-3p that mediated by macrophages-derived EVs on atherosclerosis (AS) by targeting small mothers against decapentaplegic 7 (Smad7). Methods EVs were extracted from M1 macrophages and identified. ApoE-/- mice were treated with EVs, EVs containing miR-185-3p inhibitor or mimic, then the pathological changes of mouse aorta were observed. The levels of blood lipid, ce...
#1Lin Sun (SPU: Shenyang Pharmaceutical University)H-Index: 1
#2Min Zhao (SPU: Shenyang Pharmaceutical University)H-Index: 8
Last. Chunjie Zhao (SPU: Shenyang Pharmaceutical University)H-Index: 6
view all 6 authors...
Shaoyao Gancao decoction (SGD) is a famous Chinese traditional prescription for treating liver injury. In this research, we investigated the liver protective effects of SGD and its metabolic mechanisms by 1 H-NMR and UPLC-MS. Serum biochemical indicators and histopathological methods werae used to identify the status of SGD in treating liver injury. An OPLS-DA method was used to screen potential differential metabolic markers, and the MetaboAnalyst and KEGG PATHWAY databases were used to find re...
1 CitationsSource