Egr2 drives the differentiation of Ly6Chi monocytes into fibrosis-promoting macrophages in metabolic dysfunction-associated steatohepatitis in mice

被引：2

作者：

Iwata, Ayaka ^{[1
]}

Maruyama, Juri ^{[1
]}

Natsuki, Shibata ^{[1
]}

Nishiyama, Akira ^{[2
]}

Tamura, Tomohiko ^{[2
,3
]}

Tanaka, Minoru ^{[4
]}

Shichino, Shigeyuki ^{[5
]}

Seki, Takao ^{[6
]}

Komai, Toshihiko ^{[7
]}

Okamura, Tomohisa ^{[7
]}

Fujio, Keishi ^{[7
]}

Tanaka, Masato ^{[1
]}

Asano, Kenichi ^{[1
]}

机构：

[1] Tokyo Univ Pharm & Life Sci, Sch Life Sci, Lab Immune Regulat, Tokyo 1920392, Japan

[2] Yokohama City Univ, Grad Sch Med, Dept Immunol, Yokohama, Kanagawa 2360004, Japan

[3] Yokohama City Univ, Adv Med Res Ctr, Yokohama, Kanagawa 2360004, Japan

[4] Res Inst Natl Ctr Global Hlth & Med, Dept Regenerat Med, Tokyo 1628655, Japan

[5] Tokyo Univ Sci, Res Inst Biomed Sci, Div Mol Regulat Inflammatory & Immune Dis, Chiba 2780022, Japan

[6] Toho Univ, Dept Biochem, Sch Med, Tokyo 1438540, Japan

[7] Univ Tokyo, Grad Sch Med, Dept Allergy & Rheumatol, Tokyo 1130033, Japan

来源：

COMMUNICATIONS BIOLOGY | 2024年 / 7卷 / 01期

关键词：

LIVER-DISEASE; KUPFFER CELLS; DISTINCT; INJURY;

D O I：

10.1038/s42003-024-06357-5

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Metabolic dysfunction-associated steatohepatitis (MASH), previously called non-alcoholic steatohepatitis (NASH), is a growing concern worldwide, with liver fibrosis being a critical determinant of its prognosis. Monocyte-derived macrophages have been implicated in MASH-associated liver fibrosis, yet their precise roles and the underlying differentiation mechanisms remain elusive. In this study, we unveil a key orchestrator of this process: long chain saturated fatty acid-Egr2 pathway. Our findings identify the transcription factor Egr2 as the driving force behind monocyte differentiation into hepatic lipid-associated macrophages (hLAMs) within MASH liver. Notably, Egr2-deficiency reroutes monocyte differentiation towards a macrophage subset resembling resident Kupffer cells, hampering hLAM formation. This shift has a profound impact, suppressing the transition frombenign steatosis to liver fibrosis, demonstrating the critical pro-fibrotic role played by hLAMs in MASH pathogenesis. Long-chain saturated fatty acids that accumulate in MASH liver emerge as potent inducers of Egr2 expression in macrophages, a process counteracted by unsaturated fatty acids. Furthermore, oral oleic acid administration effectively reduces hLAMs in MASH mice. In conclusion, our work not only elucidates the intricate interplay between saturated fatty acids, Egr2, and monocyte-derived macrophages but also highlights the therapeutic promise of targeting the saturated fatty acid-Egr2 axis in monocytes for MASH management.

引用

页数：16