Ion and Water Transport in Neutrophil Granulocytes and Its Impairment during Sepsis

Abstract

Neutrophil granulocytes are the vanguard of innate immunity in response to numerous pathogens. Their activity drives the clearance of microbe- and damage-associated molecular patterns, thereby contributing substantially to the resolution of inflammation. However, excessive stimulation during sepsis leads to cellular unresponsiveness, immunological dysfunction, bacterial expansion, and subsequent multiple organ dysfunction. During the short lifespan of neutrophils, they can become significantly activated by complement factors, cytokines, and other inflammatory mediators. Following stimulation, the cells respond with a defined (electro-)physiological pattern, including depolarization, calcium influx, and alkalization as well as with increased metabolic activity and polarization of the actin cytoskeleton. Activity of ion transport proteins and aquaporins is critical for multiple cellular functions of innate immune cells, including chemotaxis, generation of reactive oxygen species, and phagocytosis of both pathogens and tissue debris. In this review, we first describe the ion transport proteins and aquaporins involved in the neutrophil ion-water fluxes in response to chemoattractants. We then relate ion and water flux to cellular functions with a focus on danger sensing, chemotaxis, phagocytosis, and oxidative burst and approach the role of altered ion transport protein expression and activity in impaired cellular functions and cell death during systemic inflammation as in sepsis.

Keywords: NADPH oxidase; NHE1; calcium; cell death; chemotaxis; intracellular pH; neutrophil granulocytes; sepsis.

Figure 1

Simplified summary of the response of neutrophils upon stimulation with chemoattracttants with a focus on the well-studied C5a-C5aR1 axis. The anaphylatoxin C5a induces an increase in intracellular Ca²⁺, depolarization, and changes in cellular pH and size. fMLF induces similar signaling. AQP9-regulation has hitherto only been demonstrated for fMLF. SOCE = store-operated calcium entry, STIM1 = stromal interaction molecule 1, ER = endoplasmic reticulum, IP₃R = inositol 1,4,5-trisphosphate receptor, IL-R = interleukin receptor, C5a = complement factor 5a, C5aR1 = C5a receptor 1, AQP9 = aquaporin 9, CaM = calmodulin, PKC = protein kinase C, NHE1 = sodium-proton exchanger 1, MCT = monocarboxylate transporter, Glu = glucose, GLUT1 = glucose transporter 1, NOX = NADPH oxidase, H_v1 = voltage-sensing domain only protein, MAMP = microbial-associated molecular pattern, fMLF = N-formylmethionyl-leucyl-phenylalanine, fMLF-R = fMLF receptor, TLR = toll-like receptor.

Figure 2

During sepsis, microbe-associated molecular patterns (MAMPs) and damage-associated molecular patterns (DAMPs) may alter various homeostatic balances. The resulting electro-physiological changes including alterations of the intracellular pH (pH_i) will affect the inflammatory response of innate immunity and in consequence, vital cell functions. The mounted immune response including the feed-in of MAMPs and DAMPs will further affect cellular electrophysiology, which finally may form a vicious circle resulting in cellular dysfunction and death.