The voltage-gated potassium channel KV1.3 regulates neutrophil recruitment during inflammation

Abstract

Aims Neutrophil trafficking within the vasculature strongly relies on intracellular calcium signaling. Sustained Ca2+ influx into the cell requires a compensatory efflux of potassium to maintain membrane potential. Here, we aimed to investigate whether the voltage-gated potassium channel KV1.3 regulates neutrophil function during the acute inflammatory process by affecting sustained Ca2+ signaling. Methods and results Using in vitro assays and electrophysiological techniques, we show that KV1.3 is functionally expressed in human neutrophils regulating sustained store operated Ca2+ entry (SOCE) through membrane potential stabilizing K+ efflux. Inhibition of KV1.3 on neutrophils by the specific inhibitor 5-(4-Phenoxybutoxy)psoralen (PAP-1) impaired intracellular Ca2+ signaling, thereby preventing cellular spreading, adhesion strengthening and appropriate crawling under flow conditions in vitro. Using intravital microscopy, we show that pharmacological blockade or genetic deletion of KV1.3 in mice decreased neutrophil adhesion in a blood flow dependent fashion in inflamed cremaster muscle venules. Furthermore, we identified KV1.3 as a critical component for neutrophil extravasation into the inflamed peritoneal cavity. Finally, we also revealed impaired phagocytosis of E.coli particles by neutrophils in the absence of KV1.3. Conclusion We show that the voltage gated potassium channel KV1.3 is critical for Ca2+ signaling and neutrophil trafficking during acute inflammatory processes. Our findings do not only provide evidence for a role of KV1.3 for sustained calcium signaling in neutrophils affecting key functions of these cells, they also open up new therapeutic approaches to treat inflammatory disorders characterized by overwhelming neutrophil infiltration. Translational Perspective Neutrophils exert important immune functions during tissue injury or bacterial infection through leaving the vasculature and extravasate into affected tissues. Conversely, neutrophils trigger the pathogenesis of acute and chronic inflammatory disorders and are involved in the development and maintenance of various autoimmune diseases. Within this study, we show that the voltage-gated potassium channel KV1.3 is functionally expressed on neutrophils and affects calcium signaling thereby regulating neutrophil effector functions during immune responses. Hence, KV1.3 represents an interesting potential new target to treat unwanted excessive neutrophil invasion in various disorders ranging from autoinflammatory disorders to ischemic tissue injury.

The Voltage-Gated Hv1 H+ Channel Is Expressed in Tumor-Infiltrating Myeloid-Derived Suppressor Cells

“…Moreover, a recent electrophysiological study strongly supports that the cells we classified as PMN-MDSCs are different from neutrophils. Using electrophysiological assays, Immler and co-workers have shown that neutrophil polymorphonuclear leukocytes (PMN) functionally express voltage-gated Kv1.3 K + channels [ 61 ], in clear contrast to our whole-cell records, where Kv1.3 or any other voltage-gated K + current was missing.…”

Human neutrophils communicate remotely via glutamate-induced glutamate release

“…However, neutrophil depolarisation could also produce a robust Ca 2+ rise that was insensitive to APV (Fig. 1H), confirming the additional, voltage-dependent and NMDAR-independent routes of Ca 2+ entry, such as the voltage-gated Ca 2+ channel Kv1.3 32 .…”

Host‐microbe metatranscriptome reveals differences between acute and chronic infections in diabetes‐related foot ulcers

“…Aquaporins (AQP3 and AQP4) and GABRA1 are also induced in response to bacterial infection, functioning in proinflammatory pathways and the enhancement of antimicrobial responses respectively [27,28]. Several genes are also associated with immunoregulation, including KCNA3, which is a critical regulator of neutrophil function and promotes chemotaxis and phagocytic mechanisms [29], as well as CCK, which can be expressed by leukocytes and modulates the local and systemic inflammatory response, chemotaxis and bactericidal capacity [30,31]. Collectively, we postulate that depletion of these genes in AI-DRFUs relative to CI-DRFUs is owing to bacterial mechanisms that disrupt host cellular/immune homeostasis and cause pathogenesis.…”