Zinc depletion regulates the processing and secretion of IL-1β.
Sterile inflammation contributes to many common and serious human diseases. The pro-inflammatory cytokine interleukin-1β (IL-1β) drives sterile inflammatory responses and is thus a very attractive therapeutic target. Activation of IL-1β in sterile diseases commonly requires an intracellular multi-protein complex called the NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome. A number of disease-associated danger molecules are known to activate the NLRP3 inflammasome. We show here that depletion of zinc from macrophages, a paradigm for zinc deficiency, also activates the NLRP3 inflammasome and induces IL-1β secretion. Our data suggest that zinc depletion damages the integrity of lysosomes and that this event is important for NLRP3 activation. These data provide new mechanistic insight to how zinc deficiency contributes to inflammation and further unravel the mechanisms of NLRP3 inflammasome activation.
Faculty of Life Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK.
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Summersgill
Faculty of Life Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK.
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England
Faculty of Life Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK.
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Lopez-Castejon
Faculty of Life Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK.
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Lawrence
1] Faculty of Life Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK [2] MedImmune Ltd, Aaron Klug Building, Granta Park, Cambridge, UK.
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Luheshi
School of Computer Science, University of Manchester, Manchester, UK.
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Pahle
School of Computer Science, University of Manchester, Manchester, UK.
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Mendes
Faculty of Life Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK.
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Brough
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015032:Zinc / Q000172:deficiency*
D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D015032:Zinc