Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects
| Autor: | Miriam Kalbitz, Stephanie Denk, Sebastian Weckbach, Rebecca Wiegner, Manfred Weiss, Miriam D. Neher, David A. C. Messerer, Peter Radermacher, Markus Huber-Lang, Daniel Rittirsch, Kristina Nilsson-Ekdahl, Bo Nilsson, Josef Vogt, Anita Ignatius, John D. Lambris, Jörg Köhl, Florian Gebhard |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Neutrophils Intracellular pH Immunology Complement C5a Neutrophil Activation Calcium in biology Mice 03 medical and health sciences 0302 clinical medicine Calmodulin Sepsis Extracellular Animals Humans Immunology and Allergy Complement Activation Receptor Anaphylatoxin C5a Protein Kinase C Peroxidase biology Hydrogen-Ion Concentration Complement system Cell biology Respiratory burst Lactoferrin Glucose 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis Myeloperoxidase Lactates biology.protein Calcium Antacids Signal transduction Signal Transduction |
| Zdroj: | The Journal of Immunology. 198:4846-4854 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1700393 |
| Popis: | 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 (pHi), 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. |
| Databáze: | OpenAIRE |
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