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

<jats:title>Abstract</jats:title> <jats:p>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 (<jats:italic toggle="yes">CatE</jats:italic> <jats:sup> −/− </jats:sup>) mice were highly resistant to myelin oligodendrocyte glycoprotein (MOG<jats:sub>35-55</jats:sub>)-induced mechanical allodynia. After MOG<jats:sub>35-55</jats:sub> immunization, neutrophils immediately accumulated in the dorsal root ganglion (DRG). Adoptive transfer of MOG<jats:sub>35-55</jats:sub>-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<jats:sub>35-55</jats:sub>-stimulated <jats:italic toggle="yes">CatE</jats:italic> <jats:sup> −/− </jats:sup> neutrophils were transferred into the recipient C57BL/6 mice. MOG<jats:sub>35-55</jats:sub> 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<jats:sub>35-55</jats:sub>-stimulated neutrophils. MOG<jats:sub>35-55</jats:sub> 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.</jats:p>