Year: 2023
Type: article
Abstract: Background Human endosomal Toll-like receptors TLR7 and TLR8 recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. TLR7 and TLR8 are, respectively, encoded by adjacent X-linked genes. We previously established that TLR7 evades X chromosome inactivation (XCI) in female immune cells. Whether TLR8 also evades XCI, however, has not yet been explored. Method In the current study, we used RNA fluorescence in situ hybridization (RNA FISH) to directly visualize, on a single-cell basis, primary transcripts of TLR7 and TLR8 relative to X chromosome territories in CD14 + monocytes and CD4 + T lymphocytes from women, Klinefelter syndrome (KS) men, and euploid men. To assign X chromosome territories in cells lacking robust expression of a XIST compartment, we designed probes specific for X-linked genes that do not escape XCI and therefore robustly label the active X chromosome. We also assessed whether XCI escape of TLR8 was associated with sexual dimorphism in TLR8 protein expression by western blot and flow cytometry. Results Using RNA FISH, we show that TLR8 , like TLR7 , evades XCI in immune cells, and that cells harboring simultaneously TLR7 and TLR8 transcript foci are more frequent in women and KS men than in euploid men, resulting in a sevenfold difference in frequency. This transcriptional bias was again observable when comparing the single X of XY males with the active X of cells from females or KS males. Interestingly, TLR8 protein expression was significantly higher in female mononuclear blood cells, including all monocyte subsets, than in male cells. Conclusions TLR8 , mirroring TLR7 , escapes XCI in human monocytes and CD4 + T cells. Co-dependent transcription from the active X chromosome and escape from XCI could both contribute to higher TLR8 protein abundance in female cells, which may have implications for the response to viruses and bacteria, and the risk of developing inflammatory and autoimmune diseases.
Source: Biology of Sex Differences
Institutions: Centre National de la Recherche Scientifique, Inserm, Hôpital Purpan, Institut Toulousain des Maladies Infectieuses et Inflammatoires, Université de Toulouse, Centre Hospitalier Universitaire de Toulouse, Hôpital Larrey, Hospital for Special Surgery, Cornell University, Weill Cornell Medicine, Université Paris Cité, Institut Cochin
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,423
Funders: Scleroderma Foundation, CSL Behring, Sidaction, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Fondation des Treilles, Foundation for Research in Rheumatology, Région Occitanie Pyrénées-Méditerranée, Fonds de dotation CSL Behring pour la recherche
OpenAlex ID: W4386839549