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Elucidating an immune metabolite pathway in sepsis

Moet, Linda 2022. Elucidating an immune metabolite pathway in sepsis. PhD Thesis, Cardiff University.
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This thesis aimed to evaluate the role of the medium-chain-fatty-acid (MCFA)-GPR84 signalling axis in sepsis. Sepsis is a life-threatening condition where the dysregulated host response to an infection can lead to death by organ failure. Several bodily systems can be affected in sepsis, including metabolism on a cellular and physiological level. GPR84 is a receptor present on innate immune myeloid cells and is upregulated in response to inflammatory stimuli. In sepsis, GPR84 expression is strongly upregulated and is an integral biomarker member of a transcriptomic signature that has been shown to accurately predict sepsis in a neonatal sepsis study. The ligands that it binds comprise MCFAs with a chain length of 10 or 12 carbons. These lipids are currently understudied and their presence in relevant amounts in the human body has been doubted in the science community. Moreover, their presence in the inflammatory context, such as during infection or in sepsis, has not been studied previously. Furthermore, their potential origin, if present, remains to be elucidated as well. I hypothesize that the MCFA-GPR84 axis is a key regulated host response in sepsis. To address this hypothesis, it is pivotal to test whether MCFAs are present in the blood and whether their concentrations change in sepsis patients and if so, to determine their possible origin. To this end, I established a lipid quantification method using liquid-chromatography tandem mass spectrometry (LC-MS/MS) that was able to reliably measure MCFAs and a range of longer chain fatty acids and acylcarnitines. Employing this method on plasma samples from a sepsis cohort led to the measurement of C10:0 and C12:0, with C10:0 being significantly increased in sepsis and C12:0 significantly decreased in some types of sepsis compared to controls. Notably, the measured lipid levels were heterogeneous and only a subset of patients showed increased C10:0 levels. Furthermore, I found using transcriptomic data that oloeyl-acp-hydrolase (OLAH), the gene encoding an enzyme pivotal in cellular MCFA production, is upregulated in sepsis. OLAH’s cellular role has previously been established with regards to MCFA production by the mammary gland during lactation, upregulation of OLAH in sepsis is likely caused by cortisol. I found that a synthetic glucocorticoid (dexamethasone) lead to increased OLAH gene expression in immune cell lines in vitro, in addition, the glucocorticoid receptor was found as potential transcription factor regulating OLAH in an in silico approach. Also, peripheral blood mononuclear cells were found to be able to produce C10:0 in vitro. Further analyses were conducted in relation to a broader range of lipids and their levels in the plasma of sepsis patient to determine the plasma lipid profile associated with sepsis. In these investigations I found increased short-chain and medium-chain acylcarnitines and decreased poly-unsaturated fatty acids, namely arachidonic acid and eicosapentaenoic acid. An altered plasma lipid profile seems to be indicative of sepsis and was partially shown to be associated with mortality and severity. Finally, the transcriptional regulation of GPR84 and its temporal expression pattern was examined using an in silico approach and in vitro experiments. These results indicate that GPR84 is likely a secondary immune response gene, upregulated after around 2 hours of an inflammatory stimulus in myeloid cell types. Overall, it appears that the MCFA-GPR84 signalling axis is likely activated in a subset of sepsis patients, most likely those with increased cortisol and at a higher risk of complications and mortality. This tentatively indicates that C10:0-GPR84 signalling in sepsis is detrimental to survival. In conclusion, the data of my thesis supports the hypothesis that the MCFA-GPR84 signalling axis is a key regulated host response with the limitation that this is likely only the case in a subset of patients. In these patients though this signalling axis could likely be a mediator of the increased mortality observed in patients with strongly elevated cortisol.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 5 September 2023
Last Modified: 06 Sep 2023 09:46

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