title: Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome.
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.
  
  
  CONCLUSIONS
  Acidic pH represents a novel danger signal alerting the innate immunity.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland. kristiina.rajamaki@helsinki.fi
authors.forename: Kristiina
authors.initials: K
authors.lastname: Rajamäki
authors.forename: Tommy
authors.initials: T
authors.lastname: Nordström
authors.forename: Katariina
authors.initials: K
authors.lastname: Nurmi
authors.forename: Karl E O
authors.initials: KE
authors.lastname: Åkerman
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
authors.forename: Katariina
authors.initials: K
authors.lastname: Öörni
authors.forename: Kari K
authors.initials: KK
authors.lastname: Eklund
mesh_terms: D000138:Acidosis / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003470:Culture Media; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D045604:Extracellular Fluid / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011188:Potassium / Q000378:metabolism; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D015533:Transcriptional Activation
chemical_list: D002352:Carrier Proteins; D003470:Culture Media; D016207:Cytokines; D058847:Inflammasomes; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D018942:Macrolides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D054328:Proton Pump Inhibitors; C040929:bafilomycin A1; D020170:Caspase 1; D011188:Potassium
keywords: Acidosis; Inflammasome; Inflammation; Innate Immunity; Interleukin; Macrophages; Nod-like Receptors (NLR)