| RRC ID |
86994
|
| 著者 |
Funagura N, Koga T, Etoh K, Hong S, Ichiyasu H, Fujijwara Y, Yasunaga KI, Usuki S, Noda A, Sagara A, Hino S, Komohara Y, Sakagami T, Inoue T, Nakao M.
|
| タイトル |
Histone demethylase KDM7A negatively regulates fibrotic macrophage polarization and lung fibrosis progression.
|
| ジャーナル |
Commun Biol
|
| Abstract |
Macrophage polarization shapes immune responses in inflammation and fibrosis, yet the epigenetic mechanisms restraining pathogenic states remain unclear. Here, we identify lysine-specific demethylase 7 A (KDM7A) as an epigenetic suppressor of a profibrotic macrophage (Fib-Mac). Using macrophage assays, single-cell RNA sequencing of Kdm7a-knockout mice, and lung tissue from fibrosis patients, we show that Kdm7a loss drives transcriptional and metabolic reprogramming toward Fib-Mac states. Kdm7a-knockout mice exhibit exacerbated bleomycin-induced lung fibrosis with the expansion of Fib-Mac populations. Mechanistically, we identify toll-like receptor 8 (TLR8) as a suppressor of Fib-Mac polarization whose expression is regulated by KDM7A via the repressive mark H3K27me2 at its enhancer. Notably, macrophage Kdm7a and Tlr8 expression declines with age in male mice, consistent with clinical risk patterns. These findings uncover an epigenetic mechanism restraining disease-driving macrophage states and suggest the KDM7A-TLR8 axis as a potential therapeutic target in fibrotic disorders.
|
| 巻・号 |
9(1)
|
| 公開日 |
2026-1-23
|
| DOI |
10.1038/s42003-026-09610-1
|
| PII |
10.1038/s42003-026-09610-1
|
| PMID |
41578150
|
| PMC |
PMC12932667
|
| MeSH |
Animals
Bleomycin
Disease Progression
Epigenesis, Genetic
Histone Demethylases* / genetics
Histone Demethylases* / metabolism
Humans
Jumonji Domain-Containing Histone Demethylases* / genetics
Jumonji Domain-Containing Histone Demethylases* / metabolism
Macrophages* / metabolism
Macrophages* / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Pulmonary Fibrosis* / chemically induced
Pulmonary Fibrosis* / genetics
Pulmonary Fibrosis* / metabolism
Pulmonary Fibrosis* / pathology
|
| リソース情報 |
| 遺伝子材料 |
pENTR4-H1tetOx1 (RDB07916)
CS-RfA-ETBsd (RDB07917)
pCAG-HIVgp (RDB04394)
pCMV-VSV-G-RSV-Rev (RDB04393) |
