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Title: The role of mitochondria in innate immunity and inflammation
Author: Widdrington, John David
ISNI:       0000 0004 5994 4030
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2016
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Deactivation of blood monocytes during sepsis is associated with increased mortality and susceptibility to secondary infections. Septic monocytes may also have mitochondrial DNA (mtDNA) depletion and mitochondrial respiratory dysfunction. Two principal approaches explored the link between these phenomena in THP-1 cells, a human leukaemia cell line resembling monocytes, to test the hypothesis that mtDNA depletion is important in the pathophysiology of monocytic cell immune deactivation. Firstly, the consequences of immune deactivation for mitochondria was assessed using an endotoxin tolerance model in which repeated exposures to lipopolysaccharide (LPS) trigger diminishing inflammatory responses. In parallel with the induction of endotoxin tolerance, LPS treatment lead to increased mitochondrial respiration due to the activation of mitochondrial biogenesis. These results could not be confirmed in healthy volunteers following inhalation of LPS as this model failed to induce endotoxin tolerance in blood monocytes. Secondly, the effects of depleting mtDNA, by treatment with ethidium bromide or transfection with short-interfering RNA targeted against mitochondrial transcription factor A, on immunity were measured. THP-1 cells with mtDNA depletion displayed the key phenotypic feature of deactivated septic monocytes, a decreased LPS-induced release of the pro-inflammatory cytokine tumour necrosis factor-α. Furthermore, there were significant alterations in the nuclear transcriptome of mtDNA-depleted THP-1 cells, with a particular inhibition of key innate immune signalling pathways and a marked blunting of the transcriptomic response to LPS. These investigations confirm that there are complex but vital links between mitochondria and innate immunity. Compensatory responses following an inflammatory insult include the simultaneous induction of mitochondrial biogenesis and shift to an anti-inflammatory phenotype. Moreover, when sepsis disrupts mitochondrial homeostasis the negative effects of mtDNA depletion on innate immunity may exacerbate monocyte immune deactivation. Further investigations should focus on exploring the fundamental processes coupling mitochondria with immunity and confirming these findings in blood monocytes during sepsis.
Supervisor: Not available Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available