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The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation

Triantafilou, K., Hughes, T. R., Triantafilou, M. and Morgan, B. P. 2013. The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation. Journal of Cell Science 126 (13) , pp. 2903-2913. 10.1242/jcs.124388

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Abstract

The membrane attack complex of complement (MAC), apart from its classical role of lysing cells, can also trigger a range of non-lethal effects on cells, acting as a drive to inflammation. In the present study, we chose to investigate these non-lethal effects on inflammasome activation. We found that, following sublytic MAC attack, there is increased cytosolic Ca2+ concentration, at least partly through Ca2+ release from the endoplasmic reticulum lumen via the inositol 1,4,5-triphosphate receptor (IP3R) and ryanodine receptor (RyR) channels. This increase in intracellular Ca2+ concentration leads to Ca2+ accumulation in the mitochondrial matrix via the ‘mitochondrial calcium uniporter’ (MCU), and loss of mitochondrial transmembrane potential, triggering NLRP3 inflammasome activation and IL-1β release. NLRP3 co-localises with the mitochondria, probably sensing the increase in calcium and the resultant mitochondrial dysfunction, leading to caspase activation and apoptosis. This is the first study that links non-lethal effects of sublytic MAC attack with inflammasome activation and provides a mechanism by which sublytic MAC can drive inflammation and apoptosis.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: Company of Biologists
ISSN: 0021-9533
Date of Acceptance: 27 March 2013
Last Modified: 30 Aug 2019 20:55
URI: http://orca-mwe.cf.ac.uk/id/eprint/116742

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