Experimental autoimmune neuritis (EAN) is a CD4+ T-cell-mediated autoimmune inflammatory
demyelinating disease of the peripheral nervous system. It has been replicated in an animal model of human inflammatory demyelinating
polyradiculoneuropathy,
Guillain-Barré syndrome. In this study, we evaluated the therapeutic efficacy of a selective inhibitor of the immunoproteasome subunit, low-MW
polypeptide 7 (PR-957) in rats with EAN. Our results showed that
PR-957 significantly delayed onset day, reduced severity and shortened duration of EAN, and alleviated
demyelination and inflammatory infiltration in sciatic nerves. In addition to significantly regulating expression of the
cytokine profile,
PR-957 treatment down-regulated the proportion of proinflammatory T-helper (Th)17 cells in sciatic nerves and spleens of rats with EAN. Data presented show the role of
PR-957 in the
signal transducer and activator of transcription 3 (STAT3) pathway.
PR-957 not only decreased expression of
IL-6 and
IL-23 but also led to down-regulation of STAT3 phosphorylation in CD4+ T cells. Regulation of the STAT3 pathway led to a reduction in
retinoid-related
orphan nuclear receptor γ t and
IL-17 production. Furthermore, reduction of STAT3 phosphorylation may have directly suppressed Th17-cell differentiation. Therefore, our study demonstrates that
PR-957 could potently alleviate
inflammation in rats with EAN and that it may be a likely candidate for treating
Guillain-Barré syndrome.-Liu, H., Wan, C., Ding, Y., Han, R., He, Y., Xiao, J., Hao, J.
PR-957, a selective inhibitor of immunoproteasome subunit low-MW
polypeptide 7, attenuates
experimental autoimmune neuritis by suppressing Th17-cell differentiation and regulating
cytokine production.