Signal transducer and activator of transcription (STAT) 3 inhibition delays the onset of lupus nephritis in MRL/lpr mice

- STAT3 is upregulated in SLE and lupus prone mice.
- STAT3 plays a role in T:B cell cross-talk, Th17 generation and T cell migration.
- Stattic, a small molecule that blocks STAT3 mitigates murine lupus nephritis.
- Stattic inhibits T cell migration in vitro.

The transcription factor STAT3 is overexpressed and hyperactivated in T cells from SLE patients. STAT3 plays a central role in T cell differentiation into Th17 and T follicular helper cells, two subsets that orchestrate autoimmune responses in SLE. Moreover, STAT3 is important in chemokine-mediated T cell migration. To better understand its role in SLE, we inhibited STAT3 in lupus-prone mice using the small molecule Stattic. Stattic-treated mice exhibited delayed onset of proteinuria (3 weeks later than controls), and had lower levels of anti-dsDNA antibodies and inflammatory cytokines. Inhibitor treatment reduced lymphadenopathy, resulted in a 3-fold decrease in total T cell number, and a 4-fold decrease in the numbers of T follicular helper cells. In vitro experiments showed that Stattic-treated T cells exhibited decreased proliferation and a decrease in ability to migrate to CXCL12. We propose that STAT3 inhibition represents a therapeutic target in SLE, particularly lupus nephritis.