Proton channel HVCN1 is required for effector functions of mouse eosinophils

Abstract

BackgroundProton currents are required for optimal respiratory burst in phagocytes. Recently, HVCN1 was identified as the molecule required for the voltage-gated proton channel activity associated with the respiratory burst in neutrophils. Although there are similarities between eosinophils and neutrophils regarding their mechanism for respiratory burst, the role of proton channels in eosinophil functions has not been fully understood.ResultsIn the present study, we first identified the expression of the proton channel HVCN1 in mouse eosinophils. Furthermore, using HVCN1-deficient eosinophils, we demonstrated important cell-specific effector functions for HVCN1. Similar to HVCN1-deficient neutrophils, HVCN1-deficient eosinophils produced significantly less reactive oxygen species (ROS) upon phorbol myristate acetate (PMA) stimulation compared with WT eosinophils. In contrast to HVCN1-deficient neutrophils, HVCN1-deficient eosinophils did not show impaired calcium mobilization or migration ability compared with wild-type (WT) cells. Uniquely, HVCN1-deficient eosinophils underwent significantly increased cell death induced by PMA stimulation compared with WT eosinophils. The increased cell death was dependent on NADPH oxidase activation, and correlated with the failure of HVCN1-deficient cells to maintain membrane polarization and intracellular pH in the physiological range upon activation.ConclusionsEosinophils require proton channel HVCN1 for optimal ROS generation and prevention of activation-induced cell death.

Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives

“…Consequently, neutrophils lacking Hv1 channel displayed a diminished ability to migrate in vitro in response to the chemoattractant N-formyl-Met-Ile-Val-Ile-Leu bacterial peptide (El Chemaly et al, 2010). Afterward, Zhu et al (2013) corroborated these findings in an in vivo model of peritonitis induced by intraperitoneal injection of thioglycollate. In this experimental setting, the number of neutrophils infiltrating the peritoneal cavity was reduced twofold in Hv1-deficient mice compared with wild-type littermates, indicating that Hv1 channel regulates neutrophils migration toward the sites of inflammation in vivo (Zhu et al, 2013).…”

“…Supporting this idea though, Kasahara et al (2016) showed that neutrophils lacking GM-CSF receptor signaling had reduced NOX activity, and consequently, their ability to kill Aspergillus fumigatus during respiratory burst was impaired, suggesting that a GM-CSFmediated mechanism of Hv1/NOX regulation could apply likewise in neutrophils. Hv1 also has an important role in the migration of neutrophils toward the sites of inflammation (El Chemaly et al, 2010;Zhu et al, 2013). This function of Hv1 controlling neutrophil migration might very well apply in the context of the TME, because it is a site of inflammation where many cytokines (TNF-a, IFN-g) and chemokines (CXCL2, CXCL1, CCL3, CXCL6) are released to attract neutrophils (Fridlender and Albelda, 2012) (Fig.…”

“…3B). Additionally, the migration of neutrophils toward the sites of inflammation is regulated by Hv1 channel (El Chemaly et al, 2010;Zhu et al, 2013), suggesting that in tumor-bearing hosts, the inhibition of Hv1 could lead to a reduced intratumoral infiltration of TANs (Fig. 3B).…”

Oxygen Increases Lung Inflammatory Response in Spontaneous One-Lung Ventilation in Rabbits: A Prospective Randomized Experimental Study

“…Existing evidence shows that there is an important link between hypoxia and eosinophil function [19]; hypoxic stress induces the transcription of several factors, like the hypoxia inducible factor (HIF-1), responsible for oxygen homeostasis [20,21], and changes in eosinophil cellular profile enhancing its ability to migrate thru blood vessels, decreasing cellular apoptosis, and prolonging its half-life [19,22,23].…”

Moving gating charges through the gating pore in a Kv channel voltage sensor

“…energy landscape | kinetic model | global fit M embrane proteins controlled by the membrane potential are ubiquitous among phyla and are involved in a variety of fundamental biological tasks such as action potential generation and propagation, pacemaker activity, insulin secretion, G proteins and lipid signaling, innate immunity, and cell homeostasis (1)(2)(3)(4)(5)(6)(7)(8). In most of these proteins, voltage sensitivity is conferred by small structural modules called voltage sensor domains (VSDs) that encompass four transmembrane helices S1-S4 (9).…”