Smad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl<sub>4</sub> Exposure in Mice

Myeloid cells play an essential role in the maintenance of liver homeostasis, as well as the initiation and termination of innate and adaptive immune responses. In chronic hepatic inflammation, the production of transforming growth factor beta (TGF-β) is pivotal for scarring and fibrosis induction a...

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Autores principales:	Ludmilla Unrau, Jessica Endig, Diane Goltz, Paulina Sprezyna, Hanna Ulrich, Julia Hagenstein, Bernd Geers, Karina Kaftan, Lukas Carl Heukamp, Gisa Tiegs, Linda Diehl
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	chronic liver injury CCl<sub>4</sub> Smad7 TGF-β myeloid cell inflammation Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/89314a314e2c4697a1dba9997f7b133b
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spelling	oai:doaj.org-article:89314a314e2c4697a1dba9997f7b133b2021-11-11T17:03:30ZSmad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl<sub>4</sub> Exposure in Mice10.3390/ijms2221115751422-00671661-6596https://doaj.org/article/89314a314e2c4697a1dba9997f7b133b2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11575https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Myeloid cells play an essential role in the maintenance of liver homeostasis, as well as the initiation and termination of innate and adaptive immune responses. In chronic hepatic inflammation, the production of transforming growth factor beta (TGF-β) is pivotal for scarring and fibrosis induction and progression. TGF-β signalling is tightly regulated via the Smad protein family. Smad7 acts as an inhibitor of the TGF-β-signalling pathway, rendering cells that express high levels of it resistant to TGF-β-dependent signal transduction. In hepatocytes, the absence of Smad7 promotes liver fibrosis. Here, we examine whether Smad7 expression in myeloid cells affects the extent of liver inflammation, injury and fibrosis induction during chronic liver inflammation. Using the well-established model of chronic carbon tetrachloride (CCl<sub>4</sub>)-mediated liver injury, we investigated the role of Smad7 in myeloid cells in LysM-Cre Smad<sup>fl/fl</sup> mice that harbour a myeloid-specific knock-down of Smad7. We found that the chronic application of CCl<sub>4</sub> induces severe liver injury, with elevated serum alanine transaminase (ALT)/aspartate transaminase (AST) levels, centrilobular and periportal necrosis and immune-cell infiltration. However, the myeloid-specific knock-down of Smad7 did not influence these and other parameters in the CCl<sub>4</sub>-treated animals. In summary, our results suggest that, during long-term application of CCl<sub>4</sub>, Smad7 expression in myeloid cells and its potential effects on the TGF-β-signalling pathway are dispensable for regulating the extent of chronic liver injury and inflammation.Ludmilla UnrauJessica EndigDiane GoltzPaulina SprezynaHanna UlrichJulia HagensteinBernd GeersKarina KaftanLukas Carl HeukampGisa TiegsLinda DiehlMDPI AGarticlechronic liver injuryCCl<sub>4</sub>Smad7TGF-βmyeloid cellinflammationBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11575, p 11575 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	chronic liver injury CCl<sub>4</sub> Smad7 TGF-β myeloid cell inflammation Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	chronic liver injury CCl<sub>4</sub> Smad7 TGF-β myeloid cell inflammation Biology (General) QH301-705.5 Chemistry QD1-999 Ludmilla Unrau Jessica Endig Diane Goltz Paulina Sprezyna Hanna Ulrich Julia Hagenstein Bernd Geers Karina Kaftan Lukas Carl Heukamp Gisa Tiegs Linda Diehl Smad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl<sub>4</sub> Exposure in Mice
description	Myeloid cells play an essential role in the maintenance of liver homeostasis, as well as the initiation and termination of innate and adaptive immune responses. In chronic hepatic inflammation, the production of transforming growth factor beta (TGF-β) is pivotal for scarring and fibrosis induction and progression. TGF-β signalling is tightly regulated via the Smad protein family. Smad7 acts as an inhibitor of the TGF-β-signalling pathway, rendering cells that express high levels of it resistant to TGF-β-dependent signal transduction. In hepatocytes, the absence of Smad7 promotes liver fibrosis. Here, we examine whether Smad7 expression in myeloid cells affects the extent of liver inflammation, injury and fibrosis induction during chronic liver inflammation. Using the well-established model of chronic carbon tetrachloride (CCl<sub>4</sub>)-mediated liver injury, we investigated the role of Smad7 in myeloid cells in LysM-Cre Smad<sup>fl/fl</sup> mice that harbour a myeloid-specific knock-down of Smad7. We found that the chronic application of CCl<sub>4</sub> induces severe liver injury, with elevated serum alanine transaminase (ALT)/aspartate transaminase (AST) levels, centrilobular and periportal necrosis and immune-cell infiltration. However, the myeloid-specific knock-down of Smad7 did not influence these and other parameters in the CCl<sub>4</sub>-treated animals. In summary, our results suggest that, during long-term application of CCl<sub>4</sub>, Smad7 expression in myeloid cells and its potential effects on the TGF-β-signalling pathway are dispensable for regulating the extent of chronic liver injury and inflammation.
format	article
author	Ludmilla Unrau Jessica Endig Diane Goltz Paulina Sprezyna Hanna Ulrich Julia Hagenstein Bernd Geers Karina Kaftan Lukas Carl Heukamp Gisa Tiegs Linda Diehl
author_facet	Ludmilla Unrau Jessica Endig Diane Goltz Paulina Sprezyna Hanna Ulrich Julia Hagenstein Bernd Geers Karina Kaftan Lukas Carl Heukamp Gisa Tiegs Linda Diehl
author_sort	Ludmilla Unrau
title	Smad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl<sub>4</sub> Exposure in Mice
title_short	Smad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl<sub>4</sub> Exposure in Mice
title_full	Smad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl<sub>4</sub> Exposure in Mice
title_fullStr	Smad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl<sub>4</sub> Exposure in Mice
title_full_unstemmed	Smad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl<sub>4</sub> Exposure in Mice
title_sort	smad7 deficiency in myeloid cells does not affect liver injury, inflammation or fibrosis after chronic ccl<sub>4</sub> exposure in mice
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/89314a314e2c4697a1dba9997f7b133b
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Smad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl<sub>4</sub> Exposure in Mice

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