Abstract
Local acidosis has been demonstrated in ischemic tissues and at inflammatory sites. Acidic extracellular pH triggers NLRP3 inflammasome activation and interleukin-1β secretion in human macrophages. Acidic pH represents a novel danger signal alerting the innate immunity. 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.
Highlights
Local acidosis has been demonstrated in ischemic tissues and at inflammatory sites
We show that low pH, which frequently occurs at sites of inflammation and ischemia, represents a novel danger signal alerting the innate immunity
Human macrophages respond to acidification of their environment by activating the NLRP3 inflammasome, which leads into activation of caspase-1 and consequent maturation and secretion of the potent proinflammatory cytokines IL-1 and IL-18
Summary
Results: Acidic extracellular pH triggers NLRP3 inflammasome activation and interleukin-1 secretion in human macrophages. Acidic medium triggered pH-dependent secretion of IL-1 and activation of caspase-1 via a mechanism involving potassium efflux from the cells. Low pH may contribute to inflammation in acidosis-associated pathologies such as atherosclerosis and post-ischemic inflammatory responses Stringent control of both extra- and intracellular pH is essential for maintaining cellular biochemical reactions and tissue homeostasis. We hypothesized that acidic environment, created by actively metabolizing immune cells or hypoxia, may represent an endogenous danger signal for macrophages and trigger inflammasome activation via alterations of the intracellular milieu. We show that extracellular acidosis triggers pH-dependent secretion of mature IL-1 from cultured human macrophages via a mechanism involving cellular potassium depletion and inflammasome activation
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