Novel role of Cdc42 and RalA GTPases in TNF-α mediated secretion of CCL2

Small GTPases. 2014:5:e29260. doi: 10.4161/sgtp.29260. Epub 2014 Jun 9.

Abstract

Transendothelial migration of autoreactive leukocytes into peripheral nerves is an early pathological hallmark of acute inflammatory demyelinating polyneuropathy (AIDP), a North American and European variant of Guillain-Barré Syndrome. Whereas the clinical management of AIDP is currently limited to non-selective immune modulating therapies, recent experimental studies support selective targeting of leukocyte trafficking as a promising alternative therapeutic strategy. Here, using a combination of targeted siRNA knockdown and pharmacological inhibitors, we report a novel role of both Cdc42 and RalA GTPases in facilitating TNF-α mediated CCL2 trafficking and release from immortalized rat peripheral nerve microvascular endoneurial endothelial cells. These findings raise interest in Cdc42 and RalA GTPases as potential therapeutic targets for the management of autoimmune inflammatory peripheral nerve disease.

Keywords: Cdc42; GTPase; RalA; endothelial; siRNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors
  • Alkyl and Aryl Transferases / metabolism
  • Animals
  • Benzamides / pharmacology
  • Cells, Cultured
  • Chemokine CCL2 / metabolism*
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Peripheral Nerves / cytology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Rats
  • Tumor Necrosis Factor-alpha / pharmacology*
  • cdc42 GTP-Binding Protein / antagonists & inhibitors
  • cdc42 GTP-Binding Protein / genetics
  • cdc42 GTP-Binding Protein / metabolism*
  • rac1 GTP-Binding Protein / antagonists & inhibitors
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism
  • ral GTP-Binding Proteins / antagonists & inhibitors
  • ral GTP-Binding Proteins / genetics
  • ral GTP-Binding Proteins / metabolism*
  • rhoA GTP-Binding Protein / antagonists & inhibitors
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Benzamides
  • Chemokine CCL2
  • GGTI 298
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • Alkyl and Aryl Transferases
  • Rala protein, rat
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein
  • ral GTP-Binding Proteins
  • rhoA GTP-Binding Protein