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J Biol Chem. 2013 May 10;288(19):13410-9. doi: 10.1074/jbc.M112.426254. Epub 2013 Mar 25.

Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome.

Author information

1
Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland. kristiina.rajamaki@helsinki.fi

Abstract

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.

KEYWORDS:

Acidosis; Inflammasome; Inflammation; Innate Immunity; Interleukin; Macrophages; Nod-like Receptors (NLR)

PMID:
23530046
PMCID:
PMC3650379
DOI:
10.1074/jbc.M112.426254
[Indexed for MEDLINE]
Free PMC Article

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