BioAcyl Corp
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Rajamäki, K., Nordström, T., & Nurmi, K. (2013). Extracellular Acidosis Is a Novel Danger Signal Alerting Innate Immunity via the NLRP3 Inflammasome. Journal of Biological Chemistry, 288(19). Added by: Dr. Enrique Feoli (14/09/2025, 01:53) Last edited by: Dr. Enrique Feoli (16/09/2025, 18:24) |
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| Resource type: Journal Article DOI: 10.1074/jbc.M112.426254 ID no. (ISBN etc.): 0021-9258 BibTeX citation key: Rajamaki2013 View all bibliographic details  |
Categories: BioAcyl Corp Subcategories: Extracellular acidity Creators: Nordström, Nurmi, Rajamäki Collection: Journal of Biological Chemistry |
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| Abstract |
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Background: Local acidosis has been demonstrated in ischemic tissues and at inflammatory sites.Results: Acidic extracellular pH triggers NLRP3 inflammasome activation and interleukin-1β secretion in human macrophages.Conclusion: Acidic pH represents a novel danger signal alerting the innate immunity.Significance: Local acidosis may promote inflammation at ischemic and inflammatory sites. Local extracellular acidification has been demonstrated at sites of ischemia and inflammation. IL-1β is one of the key proinflammatory cytokines, and thus, its synthesis and secretion are tightly regulated. The NLRP3 (nucleotide-binding domain leucine-rich repeat containing family, pyrin domain containing 3) inflammasome complex, assembled in response to microbial components or endogenous danger signals, triggers caspase-1-mediated maturation and secretion of IL-1β. In this study, we explored whether acidic environment is sensed by immune cells as an inflammasome-activating danger signal.
Human macrophages were exposed to custom cell culture media at pH 7.5–6.0. Acidic medium triggered pH-dependent secretion of IL-1β and activation of caspase-1 via a mechanism involving potassium efflux from the cells. Acidic extracellular pH caused rapid intracellular acidification, and the IL-1β-inducing effect of acidic medium could be mimicked by acidifying the cytosol with bafilomycin A1, a proton pump inhibitor. Knocking down the mRNA expression of NLRP3 receptor abolished IL-1β secretion at acidic pH. Remarkably, alkaline extracellular pH strongly inhibited the IL-1β response to several known NLRP3 activators, demonstrating bipartite regulatory potential of pH on the activity of this inflammasome. The data suggest that acidic environment represents a novel endogenous danger signal alerting the innate immunity. Low pH may thus contribute to inflammation in acidosis-associated pathologies such as atherosclerosis and post-ischemic inflammatory responses.
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