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Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects
Univ Hosp Ulm, Germany.
Univ Hosp Ulm, Germany.
Univ Hosp Ulm, Germany.
Univ Hosp Ulm, Germany.
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2017 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 198, no 12, 4846-4854 p.Article in journal (Refereed) Published
Abstract [en]

During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pH(i)), we propose a direct mechanistic link between complement activation and neutrophil pHi. In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pHi by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin. Notably, the pH shift caused by C5a increased the glucose uptake and activated glycolytic flux in neutrophils, resulting in a significant release of lactate. Furthermore, C5a induced acidification of the extracellular micromilieu. In experimental murine sepsis, pHi of blood neutrophils was analogously alkalinized, which could be normalized by C5aR1 inhibition. In the clinical setting of sepsis, neutrophils from patients with septic shock likewise exhibited a significantly increased pHi. These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pHi balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.

Place, publisher, year, edition, pages
2017. Vol. 198, no 12, 4846-4854 p.
National Category
Immunology
Research subject
Biomedical Sciences, Immunology
Identifiers
URN: urn:nbn:se:lnu:diva-67105DOI: 10.4049/jimmunol.1700393ISI: 000405271300030PubMedID: 28490576OAI: oai:DiVA.org:lnu-67105DiVA: diva2:1128752
Available from: 2017-07-28 Created: 2017-07-28 Last updated: 2017-07-28Bibliographically approved

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Nilsson, BoNilsson Ekdahl, KristinaIgnatius, Anita
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CiteExportLink to record
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Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
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  • fi-FI
  • nn-NO
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  • Other locale
More languages
Output format
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