PUBLICATION

Tissue-resident trained immunity in hepatocytes protects against septic liver injury in zebrafish

Authors

Wang, Z., Liu, Y., Hu, J., You, X., Yang, J., Zhang, Y., Liu, Q., Yang, D.

ID

ZDB-PUB-240609-10

Date

2024

Source

Cell Reports 43: 114324114324 (Journal)

Registered Authors

Yang, Dahai

Keywords

CP: Immunology, H3K4me3, hepatocytes, mitophagy, pyroptosis, septic-liver injury, trained immunity, zebrafish, β-glucan

MeSH Terms

Immunity, Innate
Zebrafish*
Zebrafish Proteins*/genetics
Zebrafish Proteins*/metabolism
Animals
Mitophagy
Hepatocytes*/immunology
Hepatocytes*/metabolism
Histones/metabolism
Sepsis*/immunology
Lectins, C-Type/metabolism
beta-Glucans/pharmacology
Pyroptosis*
Liver/immunology
Liver/metabolism
Liver/pathology
Lipopolysaccharides
Trained Immunity

(all 18)

PubMed

38850536 Full text @ Cell Rep.

Abstract

Trained immunity is classically characterized by long-term functional reprogramming of innate immune cells to combat infectious diseases. Infection-induced organ injury is a common clinical severity phenotype of sepsis. However, whether the induction of trained immunity plays a role in protecting septic organ injury remains largely unknown. Here, through establishing an in vivo β-glucan training and lipopolysaccharide (LPS) challenge model in zebrafish larvae, we observe that induction of trained immunity could inhibit pyroptosis of hepatocytes to alleviate septic liver injury, with an elevated trimethyl-histone H3 lysine 4 (H3K4me3) modification that targets mitophagy-related genes. Moreover, we identify a C-type lectin domain receptor in zebrafish, named DrDectin-1, which is revealed as the orchestrator in gating H3K4me3 rewiring-mediated mitophagy activation and alleviating pyroptosis-engaged septic liver injury in vivo. Taken together, our results uncover tissue-resident trained immunity in maintaining liver homeostasis at the whole-animal level and offer an in vivo model to efficiently integrate trained immunity for immunotherapies.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
bcl2l1	AB	chemical treatment by environment: beta-D-glucan	Long-pec to Day 6	hepatocyte	RTPCR	Fig. 5
bcl2l1	AB	primary cell culture: liver, chemical treatment by environment: beta-D-glucan	1-cell	hepatocyte	RTPCR	Fig. 4
bcl2l1	AB	chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	hepatocyte	RTPCR	Fig. 5
bcl2l1	AB	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	hepatocyte	RTPCR	Fig. 5
DsRed	gz15aTg/gz15aTg	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	liver	IFL	Fig. 2
DsRed	gz15aTg/gz15aTg	chemical treatment by environment: beta-D-glucan	Long-pec to Day 6	liver	IFL	Fig. 3
DsRed	gz15aTg/gz15aTg	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	liver	IFL	Fig. 3
DsRed	gz15aTg/gz15aTg	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide, chemical treatment by environment: HMTase Inhibitor IX	Long-pec to Day 6	liver	IFL	Fig. 3
DsRed	gz15aTg/gz15aTg	chemical treatment by environment: beta-D-glucan	Long-pec to Day 6	liver	IFL	Fig. 2
DsRed	gz15aTg/gz15aTg	chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	liver	IFL	Fig. 2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	hepatocyte bcl2l1 expression amount, ameliorated	Fig. 5
AB	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	hepatocyte gabarapa expression increased amount, abnormal	Fig. 5
AB	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	hepatocyte rab7a expression increased amount, abnormal	Fig. 5
AB	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	hepatocyte sqstm1 expression increased amount, abnormal	Fig. 5
AB	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	hepatocyte ulk1b expression increased amount, abnormal	Fig. 5
AB	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	hepatocyte mitochondrion normal object quality, ameliorated	Fig. 5
AB	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	hepatocyte mitophagy increased occurrence, abnormal	Fig. 5
AB	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	liver fabp2 expression amount, ameliorated	Fig. 1
AB	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	liver lipid droplet formation increased occurrence, ameliorated	Fig. 1
AB	chemical treatment by environment: beta-D-glucan, chemical treatment by environment: lipopolysaccharide	Long-pec to Day 6	liver lipid droplet formation increased occurrence, ameliorated	Fig. 5

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
gz15aTg	Tg(fabp10a:DsRed)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
cldc1	CRISPR1-cldc1	CRISPR
cldc1	CRISPR2-cldc1	CRISPR
cldc1	CRISPR3-cldc1	CRISPR
cldc1	CRISPR4-cldc1	CRISPR
gsdmeb	CRISPR2-gsdmeb	CRISPR

Fish

Fish
AB
AB + CRISPR1-cldc1 + CRISPR2-cldc1 + CRISPR3-cldc1 + CRISPR4-cldc1
gz15aTg/gz15aTg

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab1-H3k4me1	polyclonal			Rabbit
Ab1-H3k4me3	polyclonal			Rabbit
Ab1-H3K9me3	polyclonal			Rabbit
Ab2-mtor	polyclonal	mtor	IgG	Rabbit
Ab65-h3	polyclonal		IgG	Rabbit

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Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
EGFP	EFG	EGFP

Mapping

Wang et al., 2024 ZDB-PUB-240609-10 PMID:38850536

Tissue-resident trained immunity in hepatocytes protects against septic liver injury in zebrafish

Wang et al., 2024

ZDB-PUB-240609-10
PMID:38850536