Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis.

Pain is a frequent and disabling symptom in patients with multiple sclerosis (MS); however， the underlying mechanisms of MS-related pain are not fully understood. Here， we demonstrated that cathepsin E (CatE) in neutrophils contributes to the generation of mechanical allodynia in experimental autoimmune encephalomyelitis， an animal model of MS. We showed that CatE-deficient (CatE) mice were highly resistant to myelin oligodendrocyte glycoprotein (MOG35-55)-induced mechanical allodynia. After MOG35-55 immunization， neutrophils immediately accumulated in the dorsal root ganglion (DRG). Adoptive transfer of MOG35-55-stimulated wild-type neutrophils into the dorsal root ganglion induced mechanical allodynia in the recipient C57BL/6 mice. However， the pain threshold did not change when MOG35-55-stimulated CatE neutrophils were transferred into the recipient C57BL/6 mice. MOG35-55 stimulation caused CatE-dependent secretion of elastase in neutrophils. Behavioral analyses revealed that sivelestat， a selective neutrophil elastase inhibitor， suppressed mechanical allodynia induced by adoptively transferred MOG35-55-stimulated neutrophils. MOG35-55 directly bound to toll-like receptor 4， which led to increased production of CatE in neutrophils. Our findings suggest that inhibition of CatE-dependent elastase production in neutrophil might be a potential therapeutic target for pain in patients with MS.