title: The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation.
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 Ca(2+) concentration, at least partly through Ca(2+) release from the endoplasmic reticulum lumen via the inositol 1,4,5-triphosphate receptor (IP3R) and ryanodine receptor (RyR) channels. This increase in intracellular Ca(2+) concentration leads to Ca(2+) 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.
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. afilouK@cardiff.ac.uk
authors.forename: Kathy
authors.initials: K
authors.lastname: Triantafilou
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hughes
authors.forename: Martha
authors.initials: M
authors.lastname: Triantafilou
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
mesh_terms: D002118:Calcium / Q000819:agonists / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000276:immunology; D002462:Cell Membrane / Q000187:drug effects* / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000276:immunology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D061251:Primary Cell Culture; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D002352:Carrier Proteins; D015938:Complement Membrane Attack Complex; D058847:Inflammasomes; D053496:Inositol 1,4,5-Trisphosphate Receptors; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D019837:Ryanodine Receptor Calcium Release Channel; C034703:mitochondrial calcium uniporter; D002118:Calcium
keywords: Complement membrane attack complex; IL-1β; Inflammasome; NLRP3