Jmjd3 regulates inflammasome activation and aggravates DSS-induced colitis in mice.
Animals
Blotting, Western
Cells, Cultured
Chromatin Immunoprecipitation
Colitis
/ chemically induced
Dextran Sulfate
/ toxicity
Enzyme-Linked Immunosorbent Assay
Fluorescent Antibody Technique
Immunohistochemistry
Inflammasomes
/ immunology
Inflammatory Bowel Diseases
/ chemically induced
Jumonji Domain-Containing Histone Demethylases
/ genetics
Male
Mice
Mice, Inbred C57BL
NF-E2-Related Factor 2
/ genetics
NLR Family, Pyrin Domain-Containing 3 Protein
/ genetics
Promoter Regions, Genetic
/ genetics
RAW 264.7 Cells
RNA, Small Interfering
/ genetics
Random Allocation
Jmjd3
NLRP3
bone marrow-derived macrophages
inflammatory bowel disease
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
28
08
2019
revised:
29
12
2019
accepted:
31
12
2019
pubmed:
24
1
2020
medline:
22
1
2021
entrez:
24
1
2020
Statut:
ppublish
Résumé
The intracellular NOD-like receptor nucleotide-binding domain-like receptors Family Pyrin Domain Containing 3 (NLRP3) is a pivotal regulator of intestinal homeostasis through regulating a variety of inflammatory and autoimmune diseases. The Jumonji domain-containing 3 (Jmjd3) plays important role in inflammatory responses and thus has been proposed as a novel attractive epigenetic target for the treatment of inflammatory diseases. We here investigated whether targeting Jmjd3 regulates NLRP3 inflammasome during experimental colitis. Jmjd3 specific inhibitor GSK J4 or knocking down Jmjd3 significantly inhibited NLRP3 inflammasome activation in lipopolysaccharide (LPS) and nigericin-stimulated bone marrow-derived macrophages. Chromatin immunoprecipitation-PCR analysis validated that GSK J4 rescued the decreased repressive H3K27me3 recruitment level on the promotors of nuclear factor-erythroid 2-related factor 2 (Nrf2) in LPS plus nigericin-induced macrophages. Nrf2 knockdown abolished NLRP3 inflammasome activation. Notably, oral administration of GSK J4 attenuated the disease progression in dextran sodium sulfate-induced colitis mouse model, including reduced disease activity index, improved body weight, rescued bowel shortening and NLRP3 inflammasome activation. Overall, our study reveals that Jmjd3 is a potential epigenetic regulator for the treatment of inflammatory bowel disease (IBD), suggesting that Nrf2 is a potential target gene of Jmjd3 by mediating methylation status of trimethylated H3 lysine 27 (H3K27me3) in the promotor and is required for NLRP3 inflammasome activation, thereby providing the platform for potential future therapeutic interventions in IBD.
Identifiants
pubmed: 31971317
doi: 10.1096/fj.201902200RR
doi:
Substances chimiques
Inflammasomes
0
NF-E2-Related Factor 2
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
Nfe2l2 protein, mouse
0
RNA, Small Interfering
0
Dextran Sulfate
9042-14-2
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
Kdm6b protein, mouse
EC 1.5.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4107-4119Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
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