Conclusions
Our results demonstrate the involvement of PKM2-mediated glycolysis in Tfh cell differentiation and SLE pathogenesis, and PKM2 could be a key therapeutic target for the treatment of SLE.
Methods
We analyzed the percentage of Tfh cells and glycolysis in CD4+ T cells from SLE patients and healthy donors and performed RNA sequencing analysis of peripheral blood CD4+ T cells and differentiated Tfh cells from SLE patients. Following Tfh cell development in vitro and following treatment with PKM2 activator TEPP-46, PKM2 expression, glycolysis, and signaling pathway proteins were analyzed. Finally, diseased MRL/lpr mice were treated with TEPP-46 and assessed for treatment effects.
Results
We found that Tfh cell percentage and glycolysis levels were increased in SLE patients and MRL/lpr mice. TEPP-46 induced PKM2 tetramerization, thereby inhibiting Tfh cell glycolysis levels. On the one hand, TEPP-46 reduced the dimeric PKM2 entering the nucleus and reduced binding to the transcription factor BCL6. On the other hand, TEPP-46 inhibited the AKT/GSK-3β pathway and glycolysis during Tfh cell differentiation. Finally, we confirmed that TEPP-46 effectively alleviated inflammatory damage in lupus-prone mice and reduced the expansion of Tfh cells in vivo. Conclusions: Our results demonstrate the involvement of PKM2-mediated glycolysis in Tfh cell differentiation and SLE pathogenesis, and PKM2 could be a key therapeutic target for the treatment of SLE.