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

ABSTRACT:

ORGANISM(S): Homo Sapiens

TISSUE(S): Macrophages

PROVIDER: ST001922 | MetabolomicsWorkbench |

REPOSITORIES: MetabolomicsWorkbench

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

Project description: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.

2023-03-11 | PXD027316 | Pride