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EP300/H3K27AC/IDO1 SIGNALING AXIS REGULATES THE CROSSTALK BETWEEN TOLDCS AND T<SUB >REG</SUB> CELLS TO PROMOTE LIVER REGENERATION IN ACETAMINOPHEN-INDUCED LIVER FAILURE

Shuai Chen 1, Ziwen Tao 1, Changqing Yang 2

Affiliations

1 Tongji Hospital, School Of Medicine, Tongji University, Shanghai, China

2 Tongji University Tongji Hospital Dept. of Gastroenterology, Shanghai, China

Summary

AI Generated

Study identifies EP300-mediated regulation of tolerogenic dendritic cells via H3K27ac/IDO1 signaling as a mechanism preserving hepatic immune homeostasis and promoting repair in acetaminophen-induced liver failure.

Type 1 conventional dendritic cells (cDC1) were significantly reduced in both clinical AILF cohorts and mouse AILF models, with depletion magnitude showing dose- and duration-dependent associations with APAP exposure.
cDC1 depletion impaired regulatory T cell priming capacity, disrupted hepatic immune homeostasis, and exacerbated AILF, while intravenous tolerogenic dendritic cell injection orchestrated hepatic Treg cell infiltration, attenuated inflammation, potentiated liver regeneration, and reversed AILF pathology.
EP300-mediated histone 3 lysine 27 acetylation in the IDO1 promoter region enforced stable tolerogenic states of cDC1, which then initiated tryptophan catabolism to generate kynurenine metabolites triggering Treg cell differentiation and functional maturation.
The therapeutic effect of tolerogenic dendritic cells was abolished after Treg cell depletion in Foxp3-DTR mice, and CD11c-cre-IDO1-f/f mice with APAP exposure had less Treg cell recruitment and worse phenotype.
This research is relevant to investigators exploring immune-mediated mechanisms and potential therapeutic targets in acetaminophen-induced liver failure.

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This summary was generated by an AI large language model based on the content transcript. It is for informational purposes only and should not be considered a substitute for clinical judgment. Always rely on your professional expertise and the full clinical context when making clinical decisions.

Abstract

Introduction

Acetaminophen-induced liver failure (AILF) has a high fatality rate and limited therapeutic approaches at present. Type 1 conventional dendritic cells (cDC1) are one of the major subgroups of cDCs in the liver, which is not only an important type in initiating adaptive immune response, but also can promote the generation, stability and function of Regulatory T (T_reg) cells through various mechanisms. cDC1 maintains liver immune homeostasis by regulating the balance between immune activation and tolerance. Nevertheless, the precise involvement and mechanistic contributions of hepatic cDCs in AILF remain to be elucidated.

Aims & Methods

Multiplex Immunohistochemistry (mIHC), flow cytometry, spatial transcriptomics (ST), single-cell RNA sequencing (scRNA-seq) and intravital 3D imaging were used to characterize the distribution and frequency of the cDC1. Bulk RNA-seq, metabolomic analyses, Cleavage Under Targets and Tagmentation (CUT&Tag) and Chromatin immunoprecipitation (ChIP)-qPCR assay were employed to explore the molecular mechanisms. CD11c^creXCR1^f/f, CD11c^creIDO1^f/f, CD11c^creP300^f/fand Foxp3^DTRmice, various mouse primary cells, human liver and serum samples were applied to verify the discoveries of bioinformatics analysis. Intravenous delivery of tolerogenic dendritic cells (tolDCs) was used to elucidate their regulatory effects on T_reg cells and roles in the AILF process.

Results

Our analyses revealed that the amount of cDC1 was significantly reduced across both clinical AILF cohorts and mouse AILF models, with the magnitude of depletion exhibiting dose- and duration-dependent associations with APAP exposure. mIHC, ST, scRNA-seq and intravital 3D imaging delineated that cDC1 depletion impaired T_reg cells priming capacity, ultimately disrupting hepatic immune homeostasis and exacerbating AILF. Intravenous tolDCs injection demonstrated therapeutic efficacy by orchestrating hepatic T_reg cells infiltration, attenuating inflammatory responses, potentiating liver regeneration, and ultimately reversing AILF-associated pathological manifestations. The therapeutic effect of intravenous tolDCs administration was abolished after diphtheria toxin-mediated T_reg cells depletion in Foxp3^DTRmice. CD11c^creXCR1^f/fmice andwild-type mice clearing cDC1 with XCL1-antibody had exacerbated liver pathology. Mechanistically, EP300-mediated histone 3 lysine 27 acetylation (H3K27ac) in IDO1 promoter region enforced stable tolerogenic states of cDC1, these epigenetically programmed cDC1 subsequently initiated tryptophan catabolism, generating kynurenine metabolites that triggered both differentiation and functional maturation of T_reg cells. Both the DC-specific knockout and inhibition of EP300 could reduce the H3k27ac levels of IDO1. And the CD11c^creIDO1^f/fmice with APAP exposure had less T_reg cells recruitment and worse phenotype.

Conclusion

This study elucidated that EP300 orchestrated tolDCs differentiation via H3K27ac/IDO1 signaling axis, this epigenetic-metabolic cascade licensed tolDCs to recruit and activate T_reg cells, thereby preserving hepatic immune homeostasis while promoting hepatocyte proliferation and tissue repair. These findings highlight novel therapeutic targets for reversing AILF pathogenesis.

Conference

UEG Week Berlin 2025

Topics

Hepatobiliary

Submission format

Abstract

Session

Liver inflammation and injury (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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