The effects of Estrogen on the IFN signature in Lupus

Abstract

Abstract Dendritic cells (DCs) are pivotal immune regulators and are important in the pathogenesis of Systemic Lupus Erythematosus (SLE). We have previously found that DCs from female lupus-prone mice constitutively over-express Type I Interferon (IFN) responsive genes resembling the IFN Signature found in SLE patients. Since this Signature is present in pre-diseased mice, it may contribute to disease pathogenesis. Nucleic acids, major auto-antigens in lupus, are potent stimulators of innate immunity and may contribute to the IFN signature by stimulating DCs through TLR7 and 9. As SLE is ~9 times more likely to affect women than men and the onset of SLE is most often in the reproductive years of women, estrogens have been suggested to affect the IFN response. To investigate the effects of estrogen on the IFN signature, we studied conventional DCs (cDCs), from male and female Sle1,2,3 lupus prone mice or from wild type C57BL/6 mice, generated in media void of sterols with supplemental titrations of 17-beta-estradiol (E2). We have found that DCs from male pre-diseased lupus-prone mice express the IFN Signature found previously in female DCs. Furthermore, E2 stimulation, regardless of the sex of the DCs, modulates the activation of cDCs in response to TLR stimulation. Interestingly, while high levels of E2 in hormone replete conditions were capable of exacerbating the IFN signature, the difference seen between wild-type and Sle DCs in standard conditions indicates both an E2 and E2-independent exacerbation in the activation of Sle DCs.