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MicroRNA-21 can Regulate Apoptosis of CD4⁺ T Cells in Systemic Lupus Erythematosus

Tue Kruse Rasmussen, Rasmus Otkjær Bak, Thomas Andersen, Anders Dige, Christian Holm, Jacob Giehm Mikkelsen and Bent Deleuran

Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by increased
apoptosis of T cells. MicroRNA (miR-)21 has been linked to apoptosis of T cells in SLE and was recently shown to be regulated by IL-21. Our objective was to investigate the effect of miR-21 on apoptosis in CD4+ T cells and its possible regulation by IL-21 in SLE.

Methods: We investigated the capacity of IL-21 to induce miR-21 by stimulating CD4+ T cells from SLE patients and healthy controls (HCs) with IL-21. The dependency of this induction upon STAT3 was investigated by inhibition of STAT3. MicroRNA-21’s effects on apoptosis were assessed by overexpressing miR-21 in CD4+ T cells and quantification of apoptotic and dead cells.

Results: Both primary and mature forms of miR-21 were induced by IL-21 in a STAT3-dependent manner in CD4+ T cells. Induction of miR-21 by IL-21 and baseline expression levels of miR-21 were lower in CD4+ T cells from SLE patients compared to HCs. PDCD4 expression levels were increased in CD4+ T cells from SLE patients compared to HCs and correlated negatively with expression levels of miR-21. Finally, overexpression of miR-21 in CD4+ T cells from SLE patients and HCs resulted in decreased apoptosis.

Conclusion: IL-21 can regulate miR-21 expression in CD4+ T cells, and CD4+ T cells from SLE patients have low levels of miR-21 and high levels of PDCD4 compared to HCs. These findings could in part explain the increased apoptosis seen in T cells from SLE patients.