The role of toll-like receptor ligands and fatty acids in the recruitment of monocytes across liver sinusoids

Sutaria, Rupesh (2017). The role of toll-like receptor ligands and fatty acids in the recruitment of monocytes across liver sinusoids. University of Birmingham. M.D.

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The liver is continuously exposed to pathogen associated molecular patterns (PAMPs) such as microbial ligands that are transported from the gut via the portal circulation. In liver disease, microbial translocation increases and patients are at risk of sepsis and poor clinical outcomes. The gut is not only a source of microbial ligands that interact with toll-like receptors (TLRs) in the liver, but also has a role in association with diet in the uptake of fatty acids. Fatty acids also modulate the outcome from disease.
Diseased livers show an increase in TLRs. Under conditions of flow upon hepatic sinusoidal endothelium cells, stimulation of the endothelium by cell surface located TLRs increases adhesion of monocytes but not transmigration in an in vitro model of liver sinusoids. To transmigrate across hepatic endothelium efficiently, the endothelium requires priming by pro-inflammatory cytokines. Oleic acid can provide a suppressive effect on inflamed hepatic sinusoidal endothelium by reducing adhesion of monocytes. Treating monocytes with ligands to cell surface TLRs diminishes their ability to migrate across inflamed endothelium.
Tumour necrosis factor α and interferon γ treatment of hepatic sinusoidal endothelial cells followed by treatment with lipopolysaccharides show a synergistic interaction increasing the expression of TLR5 and 7 beyond what is seen treatment individually by the cytokines.
One of the fates of recruited monocytes to the liver is to differentiate into macrophages. Oleic acid is able to increase the expression of CD206, one of the markers of alternative activation on macrophages. Alternatively differentiated liver derived macrophages show increased expression of TLR5.

Type of Work: Thesis (Higher Doctorates > M.D.)
Award Type: Higher Doctorates > M.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Immunity and Infection
Funders: Other
Other Funders: University Hospitals Birmingham Charity
Subjects: R Medicine > RC Internal medicine


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