PKD regulates actin polymerization, neutrophil deformability, and transendothelial migration in response to fMLP and trauma

Christoph Wille, Tim Eiseler, Sven Thorben Langenberger, Julia Richter, Kensaku Mizuno, Peter Radermacher, Uwe Knippschild, Markus Huber-Lang, Thomas Seufferlein, Stephan Paschke

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Neutrophils are important mediators of the innate immune defense and of the host response to a physical trauma. Because aberrant infiltration of injured sites by neutrophils was shown to cause adverse effects after trauma, we investigated how neutrophil infiltration could be modulated at the cellular level. Our data indicate that protein kinase D (PKD) is a vital regulator of neutrophil transmigration. PKD phosphorylates the Cofilin-phosphatase Slingshot-2L (SSH-2L). SSH-2L in turn dynamically regulates Cofilin activity and actin polymerization in response to a chemotactic stimulus for neutrophils, for example, fMLP. Here, we show that inhibition of PKD by two specific small molecule inhibitors results in broad, unrestricted activation of Cofilin and strongly increases the F-actin content of neutrophils even under basal conditions. This phenotype correlates with a significantly impaired neutrophil deformability as determined by optical stretcher analysis. Consequently, inhibition of PKD impaired chemotaxis as shown by reduced extravasation of neutrophils. Consequently, we demonstrate that transendothelial passage of both, neutrophil-like NB4 cells and primary PMNs recovered from a hemorrhagic shock trauma model was significantly reduced. Thus, inhibition of PKD may represent a promising modulator of the neutrophil response to trauma.

Original languageEnglish
Pages (from-to)615-630
Number of pages16
JournalJournal of Leukocyte Biology
Volume104
Issue number3
DOIs
Publication statusPublished - 2018 Sep

Keywords

  • PMN
  • actin
  • cofilin
  • motility
  • protein kinase D
  • slingshot2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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  • Cite this

    Wille, C., Eiseler, T., Langenberger, S. T., Richter, J., Mizuno, K., Radermacher, P., Knippschild, U., Huber-Lang, M., Seufferlein, T., & Paschke, S. (2018). PKD regulates actin polymerization, neutrophil deformability, and transendothelial migration in response to fMLP and trauma. Journal of Leukocyte Biology, 104(3), 615-630. https://doi.org/10.1002/JLB.4A0617-251RR