Title | Altered X-chromosome inactivation of the TLR7/8 locus and heterogeneity of pDCs in systemic sclerosis. |
Publication Type | Journal Article |
Year of Publication | 2025 |
Authors | Du Y, Faz-Lopez B, Kioon MDominique, Cenac C, Pierides M, Lakin KS, Spiera RF, Chaumeil J, Truchetet M-E, Gordon JK, Guéry J-C, Barrat FJ |
Journal | J Exp Med |
Volume | 222 |
Issue | 3 |
Date Published | 2025 Mar 03 |
ISSN | 1540-9538 |
Keywords | Adult, Aged, Dendritic Cells, Female, Genetic Loci, Humans, Interferon Type I, Male, Middle Aged, RNA, Long Noncoding, Scleroderma, Systemic, Toll-Like Receptor 7, Toll-Like Receptor 8, X Chromosome Inactivation |
Abstract | Systemic sclerosis (SSc) is an autoimmune disease that has a strong female predominance. Both the X-linked TLR7 and TLR8 can induce type I IFN (IFN-I) by plasmacytoid DCs (pDCs), which can promote fibrosis. We identified five subclusters of pDCs, including ISGhigh clusters that were over-represented in SSc patients. We observed that both TLR7 and TLR8 genes escape from X chromosome inactivation (XCI) at higher frequency in pDCs of SSc patients, which was associated with changes in TLR7 protein profile. Combined DNA/RNA FISH analysis revealed that the TLR7/8 locus is preferentially located outside of the inactive X (Xi) territory when TLR7 is expressed, suggesting that higher-order loop formation is linked to TLR7/8 expression from the Xi. Furthermore, the expression levels of XIST and the transcriptional repressor SPEN were reduced in SSc pDCs. Hence, our data revealed the heterogeneity of pDCs in SSc and suggested that altered XCI at the TLR7/8 locus may contribute to the chronic IFN-I activity of pDCs in female SSc patients. |
DOI | 10.1084/jem.20231809 |
Alternate Journal | J Exp Med |
PubMed ID | 39670995 |
PubMed Central ID | PMC11639950 |
Grant List | R01 AI132447 / AI / NIAID NIH HHS / United States / / Tow Foundation / #1901175 / / Région Occitanie Pyrénées-Méditerranée / 1R01AI132447 / NH / NIH HHS / United States / / FOREUM Foundation for Research in Rheumatology / / / Scleroderma Foundation / / / Scleroderma Research Foundation / ANR-20-CE15-0014-01 / / Agence Nationale de la Recherche / |
Submitted by ljc4002 on September 10, 2025 - 2:13pm