• Xinwen Zhang, Zhou Wu, Yoshinori Hayashi, Ryo Okada, and Hiroshi Nakanishi.
• 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.
• J. Neurosci. 2014 Feb 19;34(8):3013-22.

AbstractThere 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.

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