Stat3 promotes kidney disease in Stat1-KO mice with lupus-like cGVHD (IRM11P.635)

Abstract

Abstract Lupus nephritis (LN) is one of the most serious manifestations of SLE with high incidence of morbidity and mortality. Opposing effects of activated Stat1 and Stat3 have been described for different diseases. Stat1 activation was reported upregulated in the kidney of lupus-prone mice with nephritis, while inhibition of Stat3 in the kidney attenuated kidney inflammation. The present study was undertaken to investigate the role of Stat1 in an experimental animal model of lupus. We induced bm12-B6 chronic graft-versus-host disease (cGVHD) in Stat1-KO and WT mice. WT mice developed anti-dsDNA autoantibodies starting at week 2 as expected, with a decline noted after week 4. In contrast, Stat1-KO mice exhibited a prolonged and significant increase of anti-dsDNA and anti-chromatin autoantibody responses compared to WT mice (week 4 to week 8). Enhanced IgG1 and IgG2b responses but absent IgG3 response were demonstrated in the sera of Stat1-KO mice as compared to WT mice given the same treatment. To our surprise, Stat1-KO mice developed severe nephritis starting at week 8. Three months after cGVHD-induction, 40% Stat1-KO mice were dead. Immunofluorescent staining of kidney sections from the cGVHD Stat1-KO mice revealed an enhanced glomerular Stat3 expression, which correlated with increased IL-6 expression. The observation that altered expression of Stat3 influences IL-6 expression in the glomeruli in this lupus model suggests possible molecular targets for treatment of LN.