Inflammation-driven NF-κB signaling represses ferroportin transcription in macrophages via HDAC1 and HDAC3

被引：0

作者：

Marques, Oriana ^{[1
,2
]}

Horvat, Natalie K. ^{[1
,3
]}

Zechner, Laura ^{[1
]}

Colucci, Silvia ^{[1
,2
]}

Sparla, Richard ^{[1
,2
]}

Zimmermann, Stefan ^{[4
]}

Neufeldt, Christopher J. ^{[5
,6
]}

Altamura, Sandro ^{[1
,2
]}

Qiu, Ruiyue ^{[1
]}

Muedder, Katja ^{[1
,2
]}

Weiss, Guenter ^{[7
,8
]}

Hentze, Matthias W. ^{[2
,9
]}

Muckenthaler, Martina U. ^{[1
,2
,3
,10
,11
]}

机构：

[1] Heidelberg Univ, German Ctr Lung Res, Dept Pediat Hematol Oncol & Immunol, Heidelberg, Germany

[2] Heidelberg Univ, German Ctr Lung Res, Mol Med Partnership Unit, Heidelberg, Germany

[3] Heidelberg Univ, Translat Lung Res Ctr Heidelberg, German Ctr Lung Res, Heidelberg, Germany

[4] Univ Hosp Heidelberg, Dept Infect Dis Microbiol & Hyg, Heidelberg, Germany

[5] Heidelberg Univ, Dept Infect Dis, Mol Virol, Heidelberg, Germany

[6] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA USA

[7] Med Univ Innsbruck, Dept Internal Med 2, Innsbruck, Austria

[8] Med Univ Innsbruck, Christian Doppler Lab Iron Metab & Anemia Res, Innsbruck, Austria

[9] European Mol Biol Lab, Meyerhofstr 1, D-69117 Heidelberg, Germany

[10] German Ctr Cardiovasc Res, Partner Site Heidelberg Mannheim, Heidelberg Mannheim, Germany

[11] Heidelberg Univ, Ctr Translat Biomed Iron Res, Heidelberg, Germany

来源：

BLOOD | 2025年 / 145卷 / 08期

关键词：

INTERFERON-GAMMA; IRON HOMEOSTASIS; SYNTHASE GENE; HEPCIDIN; LIPOPOLYSACCHARIDE; EXPRESSION; PATHWAY; INNATE; NRF2; VORINOSTAT;

D O I：

10.1182/blood.2023023417

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Anemia of inflammation is a prevalent comorbidity in patients with chronic inflammatory disorders. Inflammation causes hypoferremia and iron-restricted erythropoiesis by limiting ferroportin (FPN)-mediated iron export from macrophages that recycle senescent erythrocytes. Macrophage cell surface expression of FPN is reduced by hepcidininduced degradation and/or by repression of FPN (Slc40a7) transcription via cytokine and Toll-like receptor (TLR) stimulation. Although the mechanisms underlying hepcidinmediated control of FPN have been extensively studied, those inhibiting Slc40a7 messenger RNA (mRNA) expression remain unknown. We applied targeted RNA interference and pharmacological screens in macrophages stimulated with the TLR2/6 ligand FSL1 and identified critical signaling regulators of Slc40a7 mRNA repression downstream of TLRs and NF-kappa B signaling. Interestingly, the NF-kappa B regulatory hub is equally relevant for Slc40a7 mRNA repression driven by the TLR4 ligand lipopolysaccharide, the cytokine tumor necrosis factor beta/lymphotoxin-alpha (LTA), and heat-killed bacteria. Mechanistically, macrophage stimulation with heat-killed Staphylococcus aureus recruits the histone deacetylases (HDACs) HDAC1 and HDAC3 to the antioxidant response element (ARE) located in the Slc40a7 promoter. Accordingly, pretreatment with a pan-HDAC inhibitor abrogates Slc40a7 mRNA repression in response to inflammatory cues, suggesting that HDACs act downstream of NF-kappa B to repress Slc40a7 transcription. Consistently, recruitment of HDAC1 and HDAC3 to the Slc40a7 ARE after stimulation with heat-killed S aureus is dependent on NF-kappa B signaling. These results support a model in which the ARE integrates the transcriptional responses of Slc40a7 triggered by signals from redox, metabolic, and inflammatory pathways. This work identifies the long-sought mechanism of Slc40a7 transcriptional downregulation upon inflammation, paving the way for therapeutic interventions at this critical juncture.

引用

页码：866 / 880

页数：15

共 68 条

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