Abstract
SummaryChloride ion plays critical roles in modulating immunological interactions. Herein, we demonstrated that the anion channel CLIC2α mediates Cl− flux to regulate hemocytes functions in the Pacific oyster (Crassostrea gigas). Specifically, during infection by Vibrio parahemolyticus, chloride influx was activated following onset of phagocytosis. Phosphorylation of Akt was stimulated by Cl− ions entering host cells, further contributing to signal transduction regulating internalization of bacteria through the PI3K/Akt signaling pathway. Concomitantly, Cl− entered phagosomes, promoted the acidification and maturation of phagosomes, and contributed to production of HOCl to eradicate engulfed bacteria. Finally, genomic screening reveals CLIC2α as a major Cl− channel gene responsible for regulating Cl− influx in oysters. Knockdown of CLIC2α predictably impeded phagosome acidification and restricted bacterial killing in oysters. In conclusion, our work has established CLIC2α as a prominent regulator of Cl− influx and thus Cl− function in C. gigas in bacterial infection contexts.
Highlights
As a principal inorganic anion in the intra- and extracellular environments, chloride (ClÀ) is involved in an extraordinary range of physiological functions including body fluid retention/excretion, osmotic maintenance, cell volume regulation, and pH balance (Bohn and de Morais, 2017; Rodan, 2019; Wang, 2016)
We demonstrated that the anion channel CLIC2a mediates ClÀ flux to regulate hemocytes functions in the Pacific oyster (Crassostrea gigas)
Phosphorylation of Akt was stimulated by ClÀ ions entering host cells, further contributing to signal transduction regulating internalization of bacteria through the PI3K/Akt signaling pathway
Summary
As a principal inorganic anion in the intra- and extracellular environments, chloride (ClÀ) is involved in an extraordinary range of physiological functions including body fluid retention/excretion, osmotic maintenance, cell volume regulation, and pH balance (Bohn and de Morais, 2017; Rodan, 2019; Wang, 2016). Accumulating evidence has implicated transmembrane ClÀ fluxes in antimicrobial processes within immune effectors such as phagocytes, the underlying mechanisms are not fully understood (Wang, 2016). Acidification of phagosomes governs their maturation and eventual antimicrobial capacity (Bouvier et al, 1994), in which ClÀ flux is critical to phagosomal pH control and bacterial infection outcomes (Di et al, 2006). ClÀ directly participates in the production of chlorine-containing oxidants for microbial killing in host immunity. In neutrophils, myeloperoxidase (MPO), which is enriched in phagosomes, catalytically converts hydrogen peroxide (H2O2) and ClÀ into the highly potent hypochlorous acid (HOCl), which oxidatively decimates microbes via protein chlorination (Busetto et al, 2007; Rosen et al, 2002, 2009)
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