Abstract
In multiple sclerosis (MS) patients, pain is a frequent and disabling symptom. However, the underlying mechanisms of neuropathic pain in MS patients is poorly understood. In the present study, we have demonstrated that cathepsin E (CatE) in neutrophils is required for mechanical allodynia in experimental autoimmune encephalomyelitis, an animal model of MS. We show that CatE-deficient (CatE -/- ) mice were highly resistant to myelin oligodendrocyte glycoprotein (MOG 35- 55 )-induced mechanical allodynia. After MOG 35-55 immunization, neutrophils immediately accumulated in the dorsal root ganglion (DRG) where neutrophils released elastase in a CatE- dependent manner. Furthermore, sivelestat, a selective neutrophil elastase inhibitor, suppressed mechanical allodynia caused by adoptively transferred MOG 35-55 -stimulated neutrophils. Neutrophil- driven increased pain perception was mediated through the activation of protease-activated receptor 2 in DRG neurons. Activation of neutrophils by MOG 35-55 was mediated by toll-like receptor 4. Our findings suggest the mechanism of driving mechanical allodynia caused by MOG 35-55 and new strategy for preventing pain in MS patients.
