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Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2017 Jun 15; Vol. 198 (12), pp. 4846-4854. Date of Electronic Publication: 2017 May 10. - Publication Year :
- 2017
-
Abstract
- 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 <subscript>i</subscript> ), we propose a direct mechanistic link between complement activation and neutrophil pH <subscript>i</subscript> In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pH <subscript>i</subscript> 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, pH <subscript>i</subscript> 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 pH <subscript>i</subscript> These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pH <subscript>i</subscript> balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.<br /> (Copyright © 2017 by The American Association of Immunologists, Inc.)
- Subjects :
- Animals
Antacids pharmacology
Calcium metabolism
Calmodulin metabolism
Complement C5a immunology
Glucose metabolism
Humans
Hydrogen-Ion Concentration
Lactates metabolism
Lactoferrin
Mice
Neutrophils chemistry
Neutrophils drug effects
Neutrophils metabolism
Peroxidase metabolism
Protein Kinase C immunology
Protein Kinase C metabolism
Receptor, Anaphylatoxin C5a metabolism
Signal Transduction
Complement Activation
Complement C5a metabolism
Neutrophil Activation
Neutrophils immunology
Sepsis immunology
Sepsis metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 198
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 28490576
- Full Text :
- https://doi.org/10.4049/jimmunol.1700393