Role of membrane attack complex in immunometabolism and inflammasome activation

Jimenez Duran, Gisela 2022. Role of membrane attack complex in immunometabolism and inflammasome activation. PhD Thesis, School of Medicine, Cardiff University. Item availability restricted.

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Abstract

The complement system, an ancient and critical part of innate immunity, has been recently involved in novel roles other than lysis to clear pathogens, implicating regulation of the innate immune response, as well as acting as an immunometabolic regulator. Complement has been shown to contribute to metabolic reprogramming of T-cells, synoviocytes as well as cells in the CNS, however, whether this is also the case for the terminal stage in the complement activation pathways, the membrane attack complex (MAC), is unclear. MAC is upregulated in diabetic and rheumatoid arthritis patients, contributing pathologically by increasing inflammation. Previous research has highlighted that a sublytic dose of MAC can initiate NLRP3 inflammasome activation via calcium influx and loss of mitochondrial membrane potential. This thesis shows that sublytic concentrations of MAC mediate a previously undescribed perturbation in cellular energy metabolism and mitochondrial dysfunction in human monocyte-derived macrophages. This is characterised by phenotypic skewing towards glycolysis and alterations of pyruvate metabolism, as well as loss of maximal mitochondrial respiratory response, fragmented mitochondrial morphology and depleted mitochondrial membrane potential, mediating mitochondrial reactive oxygen species production and NLRP3 inflammasome activation, gasdermin D formation and pro-inflammatory cytokine release. This novel link between sublytic MAC and immunometabolism elucidates a novel signalling cascade with metabolic alterations at its centre, having direct consequences for downstream inflammatory processes, and is important for development of novel therapeutics for areas where MAC may mediate disease.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Date of First Compliant Deposit:	29 June 2023
Last Modified:	06 Jan 2024 04:27
URI:	https://orca.cardiff.ac.uk/id/eprint/160694

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