TLR7 Ligands Induce Higher IFN-α Production in Females

Abstract

IFN-α exercises multiple immune modulatory and antiviral activities and has been suggested to play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) release IFN-α upon TLR7 and TLR9 ligation. With respect to the nine times higher incidence of SLE in women and the clinical use of synthetic TLR ligands as novel immune adjuvants, we analyzed IFN-α and TNF-α production in healthy human individuals. Blood samples were incubated with synthetic TLR7 and TLR9 ligands. In three independent groups (n1 = 120, n2 = 101, and n3 = 123), analysis revealed a capacity of female PBLs to produce significantly higher IFN-α levels after TLR7 stimulation (p1 < 0.0000001, p2 < 0.0000001, and p3 < 0.0001) compared with male PBLs. In contrast, no sex differences were evident after TLR9 stimulation. TNF-α production after TLR7 stimulation and also total pDC numbers were not different between females and males. X-inactivation escape of the TLR7 gene was investigated in monoclonal B cell lines and, independently, in pDCs after cell sorting and single-cell picking, indicating regular silencing of one TLR7 allele in females. Additionally, exogenous 17β-estrogen and estrogen receptor antagonism did not indicate a significant role on TLR7-induced IFN-α production. Our data reveal for the first time a profound sex-dependent pathway of TLR7-induced IFN-α with higher production in females. These findings may explain the higher prevalence of SLE in females and the reported decreased therapeutic efficacy of synthetic TLR7 ligands in male individuals.

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.…”

“…Incomplete X-inactivation of TLR7 may contribute to the effects of sex. 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).…”

“…For HBV, the prevalence of the variant allele among chronic patients has not yet been explored. 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).…”

17β‐estradiol induces CD40 expression in dendritic cells via MAPK signaling pathways in a minichromosome maintenance protein 6–dependent manner

“…It has been reported that TLR7 ligands induced higher IFN␣ production in females (31) and that 17␤-estradiol promoted TLR4-triggered proinflammatory mediator production (32). In the present study, we demonstrated that 17␤-estradiol enhanced CD40 expression and DC maturation with or without CpG, which is the ligand of TLR9.…”

Sex differences in the GSK3β-mediated survival of adherent leukemic progenitors

“…Sex differences in immune responses have been described. For instance, higher production of interferon-a by activated peripheral blood mononuclear cells from women compared with cells from men has been described (Bergho¨fer et al, 2006). Interestingly, interferon-a restores normal b 1 -integrin-mediated inhibition of leukemic progenitor proliferation (Bhatia et al, 1996) and RACK1 has been shown to be a partner of both integrin and interferon-a receptor (Kubota et al, 2002;Kiely et al, 2008).…”