Chemokine receptors as specific anti-inflammatory targets in peripheral nerves

Chemokines are the initial mediators of leukocyte migration across concentration gradients in vitro and to sites of inflammation in vivo. Chemokines signal via specific seven-transmembrane spanning G-protein coupled receptors (GPCRs). About 50 chemokine ligands and 18 receptors have been identified to date, and several are involved in leukocyte trafficking in human inflammation. Several chemokines signal via a single receptor, while others signal via multiple receptors. This redundancy may be necessary to mediate essential biological processes in vivo. There is evidence that specific chemokines and their receptors are expressed in the peripheral nerves or cerebrospinal fluid of patients with autoimmune neuropathies such as Guillain-Barré syndrome and Chronic Inflammatory Demyelinating Polyradiculoneuropathy and their animal models. Hematogenous leukocyte trafficking and chemokine-mediated signaling has also been implicated in the generation of neuropathic pain following peripheral nerve injury. Chemokine receptors, being GPCRs, provide an attractive drug target for modulating the harmful effects of peripheral nerve inflammation. The efficacy of anti-inflammatory therapies, including treatments that restrict leukocyte migration, has been established in several inflammatory disorders such as multiple sclerosis. There are several ongoing clinical trials testing chemokine receptor antagonists as specific anti-inflammatory drugs. This review evaluates the current status of the chemokine biology of peripheral neuropathies, highlighting areas where further studies are needed and discusses potentially selective drug targets for peripheral nerve inflammation and neuropathic pain.