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Myeloid DLL4 Does Not Contribute to the Pathogenesis of Non-Alcoholic Steatohepatitis in Ldlr-/- Mice.

Jeurissen, M.L.J., Walenbergh, S.M.A., Houben, T., Hendrikx, T., Li, J., Oligschlaeger, Y., van Gorp, P.J., Gijbels, M.J.J., Bitorina, A., Nessel, I., Radtke, F., Vooijs, M., Theys, J. and Shiri-Sverdlov, R., 2016. Myeloid DLL4 Does Not Contribute to the Pathogenesis of Non-Alcoholic Steatohepatitis in Ldlr-/- Mice. PLoS One, 11 (11), -.

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DOI: 10.1371/journal.pone.0167199


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.

Item Type:Article
Uncontrolled Keywords:Adaptor Proteins, Signal Transducing ; Animals ; Calcium-Binding Proteins ; Cells, Cultured ; Disease Models, Animal ; Inflammation ; Intracellular Signaling Peptides and Proteins ; Kupffer Cells ; Liver ; Macrophages ; Membrane Proteins ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Non-alcoholic Fatty Liver Disease ; Receptors, LDL ; Signal Transduction
Group:Faculty of Health & Social Sciences
ID Code:35206
Deposited By: Symplectic RT2
Deposited On:22 Feb 2021 08:30
Last Modified:14 Mar 2022 14:26


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