Estriol Generates Tolerogenic Dendritic Cells In Vivo That Protect against Autoimmunity

Abstract

Chronic inflammation contributes to numerous diseases, and regulation of inflammation is crucial for disease control and resolution. Sex hormones have potent immunoregulatory abilities. Specifically, estrogen influences immune cells and inflammation, which contributes to the sexual dimorphism of autoimmunity and protection against disease seen during pregnancy in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Although long thought to act primarily on T cells, recent evidence demonstrated that myeloid cells, such as dendritic cells (DCs), are essential in mediating estrogen's protective effects. Estriol (E3), a pregnancy-specific estrogen, has therapeutic efficacy in MS and EAE, and we evaluated whether E3 could act exclusively through DCs to protect against the inflammatory autoimmune disease EAE. Levels of activation markers (CD80 and CD86) and inhibitory costimulatory markers (PD-L1, PD-L2, B7–H3, and B7–H4) were increased in E3 DCs. E3 DCs had decreased proinflammatory IL-12, IL-23, and IL-6 mRNA expression, increased immunoregulatory IL-10 and TGF-β mRNA expression, and a decreased ratio of IL-12/IL-10 protein production. Importantly, transfer of E3 DCs to mice prior to active induction of EAE protected them from developing EAE through immune deviation to a Th2 response. This protection was apparent, even in the face of in vitro and in vivo inflammatory challenge. In summary, our results showed that E3 generates tolerogenic DCs, which protect against the inflammatory autoimmune disease EAE. Targeted generation of tolerogenic DCs with immunomodulatory therapeutics, such as E3, has potential applications in the treatment of numerous autoimmune and chronic inflammatory diseases.

Fetal–Maternal Alignment of Regulatory T Cells Correlates with IL-10 and Bcl-2 Upregulation in Pregnancy

“…Although the exact mechanism regulating IL-10 production in pregnancy is unknown, some evidence implicates the influence of pregnancy related hormones, such as human chorionic gonadotropin, E2, and E3, which have been shown to influence IL-10 production (31,32). However, because E2 and E3 are the predominant estrogens in pregnancy (33), we measured serum IL-10 and E2 and E3 levels in maternal blood and found a modest but significant correlation between serum IL-10 and serum E2 and E3 (Fig.…”

Dimethyl Fumarate Inhibits Dendritic Cell Maturation via Nuclear Factor κB (NF-κB) and Extracellular Signal-regulated Kinase 1 and 2 (ERK1/2) and Mitogen Stress-activated Kinase 1 (MSK1) Signaling

“…DCs were isolated 3-4 weeks later. Whole spleens were processed into a single cell suspension, and CD11c ϩ DCs were then purified using CD11c magnetic bead positive selection (Miltenyi Biotec, Auburn, CA) on an AUTOMACS separator (Miltenyi Biotec) (13). Purity of DCs was verified by flow cytometry to be greater than 95%.…”

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

“…Immunoregulatory molecules and markers, including PD-L1, PD-L2, B7-H3, B7-H4, CD103 and ILT3/4, increased production of immunoregulatory cytokines and factors (e.g., IL-10, IL-1β, TGF-β, indoleamine 2,3-dioxygenase (IDO), arginase I, iNOS) or decreased production of pro-inflammatory cytokines (e.g., IL-6, IL-12, IL-15, TNF-α, IL-1α) have been described in different regDC model systems [1,[20][21][22][23][24][25]. Plasmacytoid regDCs might express CCR9 [26]; in cancer, plasmacytoid regDCs may be identified as cells expressing FOXO3 [27].…”