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Role of the Intracellular Sodium Homeostasis in Chemotaxis of Activated Murine Neutrophils.


ABSTRACT: The importance of the intracellular Ca2+ concentration ([Ca2+]i) in neutrophil function has been intensely studied. However, the role of the intracellular Na+ concentration ([Na+]i) which is closely linked to the intracellular Ca2+ regulation has been largely overlooked. The [Na+]i is regulated by Na+ transport proteins such as the Na+/Ca2+-exchanger (NCX1), Na+/K+-ATPase, and Na+-permeable, transient receptor potential melastatin 2 (TRPM2) channel. Stimulating with either N-formylmethionine-leucyl-phenylalanine (fMLF) or complement protein C5a causes distinct changes of the [Na+]i. fMLF induces a sustained increase of [Na+]i, surprisingly, reaching higher values in TRPM2-/- neutrophils. This outcome is unexpected and remains unexplained. In both genotypes, C5a elicits only a transient rise of the [Na+]i. The difference in [Na+]i measured at t = 10 min after stimulation is inversely related to neutrophil chemotaxis. Neutrophil chemotaxis is more efficient in C5a than in an fMLF gradient. Moreover, lowering the extracellular Na+ concentration from 140 to 72 mM improves chemotaxis of WT but not of TRPM2-/- neutrophils. Increasing the [Na+]i by inhibiting the Na+/K+-ATPase results in disrupted chemotaxis. This is most likely due to the impact of the altered Na+ homeostasis and presumably NCX1 function whose expression was shown by means of qPCR and which critically relies on proper extra- to intracellular Na+ concentration gradients. Increasing the [Na+]i by a few mmol/l may suffice to switch its transport mode from forward (Ca2+-efflux) to reverse (Ca2+-influx) mode. The role of NCX1 in neutrophil chemotaxis is corroborated by its blocker, which also causes a complete inhibition of chemotaxis.

SUBMITTER: Najder K 

PROVIDER: S-EPMC7506047 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Role of the Intracellular Sodium Homeostasis in Chemotaxis of Activated Murine Neutrophils.

Najder Karolina K   Rugi Micol M   Lebel Mégane M   Schröder Julia J   Oster Leonie L   Schimmelpfennig Sandra S   Sargin Sarah S   Pethő Zoltán Z   Bulk Etmar E   Schwab Albrecht A  

Frontiers in immunology 20200908


The importance of the intracellular Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) in neutrophil function has been intensely studied. However, the role of the intracellular Na<sup>+</sup> concentration ([Na<sup>+</sup>]<sub>i</sub>) which is closely linked to the intracellular Ca<sup>2+</sup> regulation has been largely overlooked. The [Na<sup>+</sup>]<sub>i</sub> is regulated by Na<sup>+</sup> transport proteins such as the Na<sup>+</sup>/Ca<sup>2+</sup>-exchanger (NCX1), Na<sup>  ...[more]

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