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J Immunol. 2017 Jun 15;198(12):4846-4854. doi: 10.4049/jimmunol.1700393. Epub 2017 May 10.

Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects.

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Institute of Clinical and Experimental Trauma-Immunology, University Hospital Ulm, 89081 Ulm, Germany.
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, 8091 Zurich, Switzerland.
Linnæus Center of Biomaterials Chemistry, Linnæus University, 391 82 Kalmar, Sweden.
Department of Orthopedic Surgery, Ulm University, University and Rehabilitation Clinics Ulm, 89081 Ulm, Germany.
Institute of Orthopedic Research and Biomechanics, Ulm University, 89081 Ulm, Germany.
Department of Traumatology, Hand, Plastic, and Reconstructive Surgery, University Hospital Ulm, 89081 Ulm, Germany.
Department of Anesthesiology, University Hospital Ulm, 89081 Ulm, Germany.
Institute of Anesthesiological Pathophysiology and Process Engineering, Ulm University, 89081 Ulm, Germany.
Institute for Systemic Inflammation Research, University of Lübeck, 23538 Lübeck, Germany.
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Institute of Clinical and Experimental Trauma-Immunology, University Hospital Ulm, 89081 Ulm, Germany;


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.

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