Content area
Full text
Received Dec 10, 2017; Revised Feb 26, 2018; Accepted Apr 1, 2018
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
1. Introduction
Innate immunity fulfils a crucial role in host defense as part of the first line of defense against pathogens. In physiological settings, polymorphonuclear leukocytes (PMN) respond to chemoattractants such as activated complement factor 5 (C5a) with cellular migration, increased apoptotic resistance, and elimination of pathogens by generation of reactive oxygen species (ROS) via activation of the NADPH oxidase [1, 2].
Systemic inflammation during sepsis or traumatic-hemorrhagic shock releases a storm of damage- and pathogen-associated molecular patterns (DAMPs and PAMPs, resp.). Although not yet completely unraveled, this plays a role in generating and releasing incompetent neutrophils with a striking discrepancy between preserved morphological integrity and functional incompetence [3, 4]. In combination with hypoxia and acidosis, this immunological dysfunction may drive the host into infectious complications and multiorgan dysfunction syndrome (MODS) resulting in a devastating mortality [3].
The complement activation product C5a interacts not only with PMN via abundantly expressed specific receptors (C5aR1 = CD88 and C5aR2 = C5L2 = GPR77) [5, 6] but also with other immune cells and epithelial cells [6]. G-protein-mediated C5aR1 signaling results predominantly in the release of intracellular calcium [5–8] in PMN, which is likely triggered by changes of membrane electrophysiology as alterations in membrane potential, ion channel permeability, and fluxes. In this context, changes in membrane potential [9–11] and transient intracellular alkalinization [12–15] represent early hallmarks of PMN activation by fMLP or phorbol myristate acetate (PMA). In contrast, neutrophils in chronic granulomatous disease are characterized by a diminished production of ROS leading to the absence of cellular depolarization and an impaired immune response [9, 16]. There is a lot of evidence that PMA- or fMLP-driven initial depolarization of PMN is mediated by NADPH oxidase activity followed by a proton-driven compensation ([11, 15–28] and more; see [29, 30] for reviews). To define detailed electrophysiological features of the cell membrane including membrane potential, patch-clamp techniques are often applied. However, in the case of electrophysiological PMN characterization, the amount of studies is surprisingly limited. In one study, the resting membrane potential of PMN was proposed to...