Altered X-chromosome inactivation of the TLR7/8 locus and heterogeneity of pDCs in systemic sclerosis.

TitleAltered X-chromosome inactivation of the TLR7/8 locus and heterogeneity of pDCs in systemic sclerosis.
Publication TypeJournal Article
Year of Publication2025
AuthorsDu 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
JournalJ Exp Med
Volume222
Issue3
Date Published2025 Mar 03
ISSN1540-9538
KeywordsAdult, 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.

DOI10.1084/jem.20231809
Alternate JournalJ Exp Med
PubMed ID39670995
PubMed Central IDPMC11639950
Grant ListR01 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 /

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