Celastrol Ameliorates EAE Induction by Suppressing Pathogenic T Cell Responses in the Peripheral and Central Nervous Systems.

ABSTRACT

Multiple sclerosis (MS) is the prototypical inflammatory demyelinating disease of the central nervous system (CNS), and MS results in physical and cognitive impairments, such as fatigue, pain, depression and bladder dysfunction. Though many therapies for MS have been developed, the safety profile and effectiveness of these therapies still need to be defined. Thus, new therapies for MS must be explored. Celastrol, a quinonemethide triterpene, is a pharmacologically active compound present in Thunder God Vine root extracts used to treat inflammatory and autoimmune diseases. Molecular studies have identified several molecular targets, which are mostly centered on the inhibition of IKK-NF-κB signaling. The animal model of experimental autoimmune encephalomyelitis (EAE) has been widely used in MS studies; thus, we tried to explore the role of celastrol in EAE development in this study. We demonstrated that the intraperitoneal injection of celastrol significantly attenuated EAE disease. Th17 cell responses in the peripheral lymph nodes in EAE mice were also inhibited by celastrol. We determined that celastroldownregulated cytokine production in bone-marrow derived dendritic cells (BMDCs). Accordingly, T cells that were co-cultured with either BMDCs pre-treated with celastrolor splenic DCs and then collected on day 7 after EAE immunizationshowed that Th17 cell polarization is suppressed in the above two situations. Moreover, celastrol was required for tissue-infiltrating DCs to sustain Th17 responses in the central nervous system (CNS). Taken together, the results of our study demonstrate that celastrol ameliorates EAE development by suppressing pathogenic Th17 responses; this finding offers a better understanding of the role of celastrol in EAE development as well as new proposals for clinical interventions.