title: Peripheral role of cathepsin S in Th1 cell-dependent transition of nerve injury-induced acute pain to a chronic pain state.
abstract: There is increasing evidence that CD4(+) T-cell-dependent responses are associated with the maintenance of neuropathic pain. However, little is known about the precise mechanism(s) underlying the activation of CD4(+) T-cells. We herein show that inhibition of cathepsin S (CatS) activity, either through genetic deletion or via a pharmacological inhibitor, Z-Phe-Leu-COCHO (Z-FL), significantly attenuated the maintenance of tactile allodynia, splenic hypertrophy, increased number of splenic CD4(+) T-cells and the final cleavage step of the MHC class II-associated invariant chain following peripheral nerve injury. It was also noted that splenectomy significantly attenuated the peripheral nerve injury-induced tactile allodynia, whereas the adoptive transfer of splenic CD4(+) T-cells from neuropathic wild-type mice significantly increased the pain level of splenectomized wild-type or CatS(-/-) mice. Furthermore, CatS deficiency or Z-FL treatment also significantly inhibited the infiltration of CD4(+) T-cells that expressed interferon-γ (IFN-γ) in the dorsal spinal cord. Signal transducer and activator of transcription 1, a molecule downstream of IFN-γ receptor activation, was activated exclusively in microglia 7 d after peripheral nerve injury. Moreover, CatS deficiency, Z-FL treatment, or splenectomy significantly attenuated the proliferation of microglia 14 d after peripheral nerve injury. These results show a peripheral pivotal role of CatS in the development of neuropathic pain through the antigen-specific activation of CD4(+) T-cells. After activation, CD4(+) T-cells infiltrate into the dorsal spinal cord and secrete IFN-γ to reactivate microglia, which contribute to the transition of acute pain to a chronic pain state.
authors.affiliation: Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan, and Japan Science and Technology Agency, CREST, Tokyo, 102-0075, Japan.
authors.forename: Xinwen
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wu
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Ryo
authors.initials: R
authors.lastname: Okada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakanishi
mesh_terms: D059787:Acute Pain / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002403:Cathepsins / Q000502:physiology*; D002469:Cell Separation; D059350:Chronic Pain / Q000503:physiopathology*; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D017353:Gene Deletion; D006930:Hyperalgesia / Q000235:genetics / Q000503:physiopathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009437:Neuralgia / Q000473:pathology; D059348:Peripheral Nerve Injuries / Q000473:pathology*; D013154:Spleen / Q000378:metabolism; D018417:Th1 Cells / Q000502:physiology*
chemical_list: D002403:Cathepsins; C028217:cathepsin S
keywords: Th1 cells; cathepsin S; dendritic cells; interferon-ganmma; microglia; neuropathic pain