title: Myeloid DLL4 Does Not Contribute to the Pathogenesis of Non-Alcoholic Steatohepatitis in Ldlr-/- Mice.
abstract: Non-alcoholic steatohepatitis (NASH) is characterized by liver steatosis and inflammation. Currently, the underlying mechanisms leading to hepatic inflammation are not fully understood and consequently, therapeutic options are poor. Non-alcoholic steatohepatitis (NASH) and atherosclerosis share the same etiology whereby macrophages play a key role in disease progression. Macrophage function can be modulated via activation of receptor-ligand binding of Notch signaling. Relevantly, global inhibition of Notch ligand Delta-Like Ligand-4 (DLL4) attenuates atherosclerosis by altering the macrophage-mediated inflammatory response. However, the specific contribution of macrophage DLL4 to hepatic inflammation is currently unknown. We hypothesized that myeloid DLL4 deficiency in low-density lipoprotein receptor knock-out (Ldlr-/-) mice reduces hepatic inflammation. Irradiated Ldlr-/- mice were transplanted (tp) with bone marrow from wild type (Wt) or DLL4f/fLysMCre+/0 (DLL4del) mice and fed either chow or high fat, high cholesterol (HFC) diet for 11 weeks. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) of DLL4f/fLysMCreWT and DLL4f/fLysMCre+/0 mice. In contrast to our hypothesis, inflammation was not decreased in HFC-fed DLL4del-transplanted mice. In line, in vitro, there was no difference in the expression of inflammatory genes between DLL4-deficient and wildtype bone marrow-derived macrophages. These results suggest that myeloid DLL4 deficiency does not contribute to hepatic inflammation in vivo. Since, macrophage-DLL4 expression in our model was not completely suppressed, it can't be totally excluded that complete DLL4 deletion in macrophages might lead to different results. Nevertheless, the contribution of non-myeloid Kupffer cells to notch signaling with regard to the pathogenesis of steatohepatitis is unknown and as such it is possible that, DLL4 on Kupffer cells promote the pathogenesis of steatohepatitis.
authors.affiliation: Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Mike L J
authors.initials: ML
authors.lastname: Jeurissen
authors.affiliation: Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Sofie M A
authors.initials: SM
authors.lastname: Walenbergh
authors.affiliation: Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Houben
authors.affiliation: Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Hendrikx
authors.affiliation: Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Jieyi
authors.initials: J
authors.lastname: Li
authors.affiliation: Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Oligschlaeger
authors.affiliation: Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: van Gorp
authors.affiliation: Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands.|Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marion J J
authors.initials: MJ
authors.lastname: Gijbels
authors.affiliation: Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Bitorina
authors.affiliation: Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Isabell
authors.initials: I
authors.lastname: Nessel
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Experimental Cancer Research Institute, Lausanne, Switzerland.
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.affiliation: Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Vooijs
authors.affiliation: Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Theys
authors.affiliation: Departments of Molecular Genetics, Pathology and Radiotherapy, School of Nutrition and Translational Research in Metabolism (NUTRIM), School for Cardiovascular Diseases (CARIM) and MAASTRO/School for Developmental Biology & Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Ronit
authors.initials: R
authors.lastname: Shiri-Sverdlov
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007249:Inflammation / Q000209:etiology / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000503:physiopathology*; D011973:Receptors, LDL / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011973:Receptors, LDL