Novel role of cdc42 and RalA GTpases in TNF-α mediated secretion of CCL2

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.