Conventional DCs from Male and Female Lupus-Prone B6.NZM Sle1/Sle2/Sle3 Mice Express an IFN Signature and Have a Higher Immunometabolism That Are Enhanced by Estrogen

Abstract

Type I interferons (IFN) are pathogenic in systemic lupus erythematosus (SLE) and were proposed to control the immunometabolism of dendritic cells (DCs). We previously reported that DCs from female lupus-prone mice constitutively overexpress IFN-responsive genes resembling the IFN signature found in SLE patients. As SLE has higher incidence in women than men, more so in women of reproductive age, estrogens are suggested to affect lupus pathogenesis. We investigated the effects of sex and estrogens on the IFN signature in conventional GM-CSF-bone marrow-derived DCs (cDCs), from male and female Triple Congenic B6.NZM.Sle1/Sle2/Sle3 (TCSle) lupus-prone mice or from wild-type C57BL/6 mice, generated with titrations of 17-beta-estradiol (E2). We found that cDCs from prediseased TCSle male mice express the IFN signature as female TCSle cDCs do. Estrogens are necessary but not sufficient to express this IFN signature, but high doses of E2 can compensate for other steroidal components. E2 stimulation, regardless of sex, modulates type I IFN-dependent and type I IFN-independent activation of cDCs in response to TLR stimulation. Finally, we found that TCSle cDCs from both sexes have elevated markers of immunometabolism and estrogens enhance the metabolic pathways in cDCs, suggesting a mechanistic link between estrogens, immunometabolism, and the IFN signature in lupus.

Ethyl Pyruvate Modulates Murine Dendritic Cell Activation and Survival Through Their Immunometabolism

“…Other reports have also supported the idea that metabolic inhibition has greater effect at the post-transcriptional level, with the inhibition of protein translation more evident than the inhibition of RNA transcription (42). We have also previously published a similar discrepancy, as we found that estrogens, by enhancing the immunometabolism of DCs, increase CXCL10 protein but not RNA levels upon TLR stimulation (1). Likewise, in this paper, the effect of EP on the decrease in RNA level is significant but less striking than that on the proteins such as the IL-12p70 and IL-10 cytokines.…”

“…We chose the TLR7 ligand R848 because it is a potent murine conventional DC (cDC) activator, which, unlike LPS (38), was not reported to induce DC death. We stained the cells ex vivo for surface lineage markers recognizing cDCs and inflammatory monocytes (iMo), two subsets of innate immune cells that are represented in vitro by the GM-CSF-DCs (1). We observed that the stimulation with R848 induced a decrease in percent splenic cDCs, which was unexpected because R848 was not previously associated with cell death, and an increase in iMo from mLNs.…”

“…Here we show for the first time that EP inhibits the activation of murine DCs, generated in culture in the presence of GM-CSF, considered a model of inflammatory DCs (1). We found that EP suppresses TLR-induced cytokine production, up-regulation of costimulatory molecules, as well as the IFN-I response.…”

“…GM-CSF-dendritic cells (which we will refer to as DCs in this paper) are an experimental model of inflammatory DCs (1), capable of sensing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), hence initiating the activation/maturation process (2–5). During activation, DCs up-regulate costimulatory molecules and secrete cytokines in order to present major histocompatibility complex (MHC)-restricted antigens to T lymphocytes in a pro-inflammatory context and induce an immune response.…”

FcγRIIb on CD11c+ cells modulates serum cholesterol and triglyceride levels and differentially affects atherosclerosis in male and female Ldlr mice

“…Estrogens are also a potential candidate for this bias as the onset of SLE is more frequent in women of childbearing age [32]. A recent study found that estrogens can increase DC maturation, enhance metabolic pathways in DCs, and modulate type I IFN-dependent and type I IFN-independent upregulation of DC activation markers in response to TLR stimulation [33]. Interestingly, estrogens have been shown to affect FcγR expression.…”