| Autor: |
Huret C; Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013 Paris, France., Ferrayé L; Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291, CNRS UMR5051, University Paul Sabatier, Toulouse, France., David A; Université Paris Cité, INSERM UMRS 976, Institut de Recherche Saint Louis, F-75010, Paris, France., Mohamed M; Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013 Paris, France., Valentin N; Université Paris Cité, CNRS, Institut Jacques Monod, F-75013, Paris, France., Charlotte F; Sorbonne University, Department of Pathological Anatomy and Cytology, Hôpital Pitié-Salpêtrière Charles Foix, F-75013, Paris, France., Savignac M; Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291, CNRS UMR5051, University Paul Sabatier, Toulouse, France., Goodhardt M; Université Paris Cité, INSERM UMRS 976, Institut de Recherche Saint Louis, F-75010, Paris, France., Guéry JC; Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291, CNRS UMR5051, University Paul Sabatier, Toulouse, France., Rougeulle C; Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013 Paris, France., Morey C; Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013 Paris, France. |
| Abstrakt: |
In mammals, males and females show marked differences in immune responses. Males are globally more sensitive to infectious diseases, while females are more susceptible to systemic autoimmunity. X-chromosome inactivation (XCI), the epigenetic mechanism ensuring the silencing of one X in females, may participate in these sex biases. We perturbed the expression of the trigger of XCI, the noncoding RNA Xist , in female mice. This resulted in reactivation of genes on the inactive X, including members of the Toll-like receptor 7 (TLR7) signaling pathway, in monocyte/macrophages and dendritic and B cells. Consequently, female mice spontaneously developed inflammatory signs typical of lupus, including anti-nucleic acid autoantibodies, increased frequencies of age-associated and germinal center B cells, and expansion of monocyte/macrophages and dendritic cells. Mechanistically, TLR7 signaling is dysregulated in macrophages, leading to sustained expression of target genes upon stimulation. These findings provide a direct link between maintenance of XCI and female-biased autoimmune manifestations and highlight altered XCI as a cause of autoimmunity. |
