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 (MOG(35-55))-induced mechanical allodynia. After MOG(35-55) immunization, neutrophils immediately accumulated in the dorsal root ganglion (DRG). Adoptive transfer of MOG(35-55)-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 MOG(35-55)-stimulated CatE(−/−) neutrophils were transferred into the recipient C57BL/6 mice. MOG(35-55) 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 MOG(35-55)-stimulated neutrophils. MOG(35-55) 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.