Dataset Information

Sublytic membrane attack complex drives glycolysis and mitochondrial dysfunction with inflammatory consequences in human monocyte-derived macrophages

ABSTRACT: The terminal stage of the complement activation pathways, the membrane attack complex (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. Here, we show that sublytic concentrations of MAC mediate a previously undescribed perturbation in cellular energy metabolism in human monocyte-derived macrophages, by phenotypic skewing towards glycolysis and upregulation of glycolysis-promoting genes. Sublytic MAC concentrations drive mitochondrial dysfunction, characterised by a fragmented mitochondrial morphology, loss of maximal respiratory response, depleted mitochondrial membrane potential as well as increased mitochondrial reactive oxygen species production. The consequences of these alterations in glycolytic metabolism and mitochondrial dysfunction lead to NLRP3 inflammasome activation, driving gasdermin D formation and IL-18 release. This novel link between sublytic MAC and immunometabolism, with direct consequences for downstream inflammatory processes, is important for development of novel therapeutics for areas where MAC may mediate disease.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell, Monocyte, Blood

SUBMITTER: Eleanor Dickinson

LAB HEAD: Roland Annan

PROVIDER: PXD027316 | Pride | 2023-03-11

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20210319_MAC_Proteomics_TMT1_HIL_40.raw	Raw
	20210319_MAC_Proteomics_TMT1_HIL_65.raw	Raw
	20210319_MAC_Proteomics_TMT1_HIL_75.raw	Raw
	20210319_MAC_Proteomics_TMT1_HIL_85.raw	Raw
	20210319_MAC_Proteomics_TMT2_HIL_40.raw	Raw

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Publications

Complement membrane attack complex is an immunometabolic regulator of NLRP3 activation and IL-18 secretion in human macrophages.

Jimenez-Duran Gisela G Kozole Joseph J Peltier-Heap Rachel R Dickinson Eleanor R ER Kwiatkowski Christopher R CR Zappacosta Francesca F Annan Roland S RS Galwey Nicholas W NW Nichols Eva-Maria EM Modis Louise K LK Triantafilou Martha M Triantafilou Kathy K Booty Lee M LM

Frontiers in immunology 20220927

The complement system is an ancient and critical part of innate immunity. Recent studies have highlighted novel roles of complement beyond lysis of invading pathogens with implications in regulating the innate immune response, as well as contributing to metabolic reprogramming of T-cells, synoviocytes as well as cells in the CNS. These findings hint that complement can be an immunometabolic regulator, but whether this is also the case for the terminal step of the complement pathway, the membrane ...[more]

PMID: 36248901

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