Salt, chloride, bleach, and innate host defense

Abstract

Salt provides 2 life-essential elements: sodium and chlorine. Chloride, the ionic form of chlorine, derived exclusively from dietary absorption and constituting the most abundant anion in the human body, plays critical roles in many vital physiologic functions, from fluid retention and secretion to osmotic maintenance and pH balance. However, an often overlooked role of chloride is its function in innate host defense against infection. Chloride serves as a substrate for the generation of the potent microbicide chlorine bleach by stimulated neutrophils and also contributes to regulation of ionic homeostasis for optimal antimicrobial activity within phagosomes. An inadequate supply of chloride to phagocytes and their phagosomes, such as in CF disease and other chloride channel disorders, severely compromises host defense against infection. We provide an overview of the roles that chloride plays in normal innate immunity, highlighting specific links between defective chloride channel function and failures in host defense.

Keywords: hypochlorous acid; myeloperoxidase; neutrophil oxidants; phagocytes.

Figure 1.. Ionic trafficking and charge balance in neutrophil phagosomes.

NOX (Nox2) transports electrons from the cytoplasm to the phagosomal lumen to reduce molecular O₂ to O₂^‒. The consequent membrane potential build-up is neutralized by cation influx through multiple cation channels or pumps, including Hv1 (VG-H⁺), voltage-gated potassium (VG-K⁺) channels, and the V-ATPase proton pump. Ferric MPO (MPO³⁺) dismutates superoxide anion to H₂O₂, whereas MPO compound I (MPO Cpd I) oxidizes Cl^‒ to produce chlorine bleach (HOCl). Phagosomal chloride acquisition is achieved through the following: 1) the PKA-activated chloride channel (e.g., CFTR channel); 2) ClCs (e.g., ClC3 2Cl^‒/H⁺ antiporter); 3) CaCCs; and 4) CCCs (e.g., KCC).

Figure 2.. Comparison of neutrophil chloride flux in normal and CF airways.

(Left) Normal airway epithelial cells express a functional CFTR channel and other chloride channels that transport chloride to the airway lumen. In addition, normal neutrophils express the normal CFTR and other chloride channels. Thus, the normal chloride supply chain ensures sufficient phagocyte chloride supplies to support sustained generation of chlorine bleach (HOCl), optimally to kill the phagocytosed pathogens. (Right) CF airway epithelial cells and neutrophils both lack functional CFTR expression, which together, limits chloride transport to neutrophil phagosomes and thereby compromises microbial killing. PMN, polymorphonuclear leukocytes.