Abstract
Two key inputs that regulate regeneration are the function of the immune system, and spatial gradients of transmembrane potential (Vmem). Endogenous bioelectric signaling in somatic tissues during regenerative patterning is beginning to be understood, but its role in the context of immune response has never been investigated. Here, we show that Vmem levels modulate innate immunity activity in Xenopus laevis embryos. We developed an assay in which X. laevis embryos are infected with a uropathogenic microorganism, in the presence or absence of reagents that modify Vmem, prior to the ontogenesis of the adaptive immune system. General depolarization of the organism’s Vmem by pharmacological or molecular genetic (ion channel misexpression) methods increased resistance to infection, while hyperpolarization made the embryos more susceptible to death by infection. Hyperpolarized specimens harbored a higher load of infectious microorganisms when compared to controls. We identified two mechanisms by which Vmem mediates immune function: serotonergic signaling involving melanocytes and an increase in the number of primitive myeloid cells. Bioinformatics analysis of genes whose transcription is altered by depolarization revealed a number of immune system targets consistent with mammalian data. Remarkably, amputation of the tail bud potentiates systemic resistance to infection by increasing the number of peripheral myeloid cells, revealing an interplay of regenerative response, innate immunity, and bioelectric regulation. Our study identifies bioelectricity as a new mechanism by which innate immune response can be regulated in the context of infection or regeneration. Vmem modulation using drugs already approved for human use could be exploited to improve resistance to infections in clinical settings.
Highlights
The vertebrate immune system is divided into two categories: innate and adaptive.[1]
We assayed a medium zebrafish embryos) and eliciting immune responses. These strains are traceable due to their harboring of a plasmid that was highly concentrated in potassium ions (60 mM), which depolarizes embryos by preventing the exit of K+ ions through encoding an unstable form of the green fluorescent protein (GFPLVA mutant) that allows the experimenters to visualize the potassium channels, by supplementing with potassium gluconate.[40,41,42]
We survival to infection was significantly increased by 11.0 +/− 2.8% in targeted chloride channels with IVM, which selectively opens EXP1-injected embryos (Fig. 1c), reinforcing our previous finding glycine receptor chloride (GlyCl) channels in the cell membrane. that the observed effects with chemical depolarization were not Since the concentration of Cl− is higher in the intracellular caused by the compounds’ direct action on bacteria and environment (40–60 mM) than in the extracellular one (10 mM), were not due to off-target effects of drug compounds, but rather treating the cell with IVM leads to its depolarization, as the were a specific consequence of bioelectric potential change in the negatively charged chloride ions exit the cell through the open host cells
Summary
The vertebrate immune system is divided into two categories: innate and adaptive.[1] The former provides the first line of defense against pathogens via the actions of surface barriers, secreted antimicrobial peptides, and a subset of blood cell types. The latter is mediated by B and T lymphocytes and relies on the memory of previous exposure to the targeted pathogenic agent. Changes in the spatial distribution of specific Vmem levels across tissues regulates various organ-level functions, including developmental organ patterning and regeneration.[11,12,13,14,15,16,17] We, hypothesized that the host’s bioelectric status could modulate the effectiveness of the innate immune response
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