The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor α signaling

Abstract

Plasmacytoid dendritic cells (pDCs) produce large amounts of type I interferons (IFN-␣/␤) in response to viral or endogenous nucleic acids through activation of their endosomal Toll-like receptors (TLR-7and TLR-9). Enhanced TLR-7-mediated IFN-␣ production by pDCs in women, compared with men, has been reported, but whether sex hormones, such as estrogens, are involved in this sex-based difference is unknown. Here we show, in humanized mice, that the TLR-7-mediated response of human pDCs is increased in female host mice relative to male. In a clinical trial, we establish that treatment of postmenopausal women with 17␤-estradiol markedly enhances TLR-7-and TLR-9-dependent production of IFN-␣ by pDCs stimulated by synthetic ligands or by nucleic acid-containing immune complexes. In mice, we found exogenous and endogenous estrogens to promote the TLR-mediated cytokine secretion by pDCs through hematopoietic expression of estrogen receptor (ER) ␣. IntroductionDendritic cells (DCs) are specialized sentinels in the immune system that detect invading pathogens and play a crucial role in orchestrating the immune responses. In response to viral infection, a specialized DC subset, plasmacytoid DCs (pDCs), produces a large amount of type I IFNs (IFN-␣/␤), which are potent anti-viral and immunostimulatory cytokines. 1 pDCs become activated to produce IFN-␣/␤ through Toll-like receptors (TLR-7 and TLR-9) within endosomal compartments that can sense viral nucleic acids. In the context of autoimmune diseases, such as systemic lupus erythematosus (SLE), these TLRs can also be inappropriately activated by self-nucleic acids complexed with autoreactive antibodies, resulting in IFN-␣ production by pDCs. 2 Activation of pDCs by endogenous DNA and RNA has been suggested to play a critical role in promoting and exacerbating SLE. 2-4 SLE patients show increased serum levels of IFN-␣ and overexpression of IFN-␣-regulated genes in blood cells, suggesting a central role for type I IFNs in disease pathogenesis. [5][6][7][8] This is supported by the observation that antinuclear antibody and SLE syndrome can develop during IFN-␣ treatment in patients with nonautoimmune disorders. 9 Likewise, IFN-␣ administration accelerates disease development and enhances disease severity in lupus-prone mouse strains. 10,11 In addition to IFN-␣, TNF-␣ has been shown to be increased in the serum of patients with active SLE disease and correlates with IFN-␣ levels. 12,13 Although pDCs can also produce TNF-␣, it is not clear whether they represent the unique source of this cytokine in SLE. 14 Cumulative evidence supports a role for sex-based differences in the pathogenesis of autoimmune and infectious diseases, which may be the result of sex hormones through their effects on innate and adaptive immunity. 15,16 A strong sex bias is observed in SLE, whose incidence is approximately 9 times higher in women relative to men. 15 Because disease onset is much more frequent in women of childbearing age, it has been hypothesized that sex steroid hormones, such as estro...

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

“…Our data adds to previous reports on the influence of sex on production of IFNα by pDCs, demonstrating that also surface maturation markers are upregulated more in female pDCs (Berghöfer et al, 2006;Meier et al, 2009;Seillet et al, 2012Seillet et al, , 2013. The effect of sex on upregulation of especially CD40 but also CD86 was respectively mostly or partially explained by the rs179008 variant allele.…”

“…Although previous studies found no evidence for incomplete or skewed X-inactivation this was recently challenged by Souyris and colleagues who reported that pDC express more TLR7 in females due to escape of X-inactivation (Schott et al, 2007a;Berghöfer et al, 2006;Souyris et al, 2018). Besides, TLR7 function may be enhanced by female hormones and/or enhanced expression of molecules downstream of TLR7 (Seillet et al, 2012(Seillet et al, , 2013Griesbeck et al, 2015). It remains unclear why possession of a heterozygous genotype offers an advantage when it comes to pDC maturation and reducing CHB risk.…”

“…pDC function is also affected by sex: male pDCs, as compared to female pDCs, produce less IFNα upon TLR7 but not TLR9 ligation (Berghöfer et al, 2006;Meier et al, 2009). This difference is believed to derive from expression differences of X-chromosomal genes downstream of TLR7, combined with hormonal effects (Seillet et al, 2012(Seillet et al, , 2013Griesbeck et al, 2015). In addition, chronic HBV (CHB) infection itself can also impair pDC function; HBV impairs IFNα secretion and other pDC functions in response to TLR9 ligation (Woltman et al, 2011;Martinet et al, 2012aMartinet et al, , 2012b.…”

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

“…It has been previously reported that estrogens enhance pDCs' immune responses after TLR-7/TLR-9 stimulation in mice [27]. In order to get a more powerful and easily detectable immune activation after administration of mtDNA, only female animals were included in our study.…”

Estradiol Promotes Functional Responses in Inflammatory and Steady-State Dendritic Cells through Differential Requirement for Activation Function-1 of Estrogen Receptor α

“…Estrogen effects are mediated by estrogen receptors (ERs) ERa and ERb, which function as ligand-induced transcription factors (3). This regulatory action of estrogens on immune responses and autoimmunity are thought to be due to a direct action on immunocompetent cells of the innate and adaptive immune systems (4), which have been recently shown to functionally express ERs, particularly ERa (5)(6)(7)(8)(9)(10)(11). Alternatively, estrogens, through their ERs, may act on precursor cells to regulate the differentiation and functions of lymphoid and myeloid cells (12)(13)(14)(15)(16)(17)(18).…”