Identification of histone deacetylase inhibitors as neutrophil recruitment modulators in zebrafish using a chemical library screen.
Dis Model Mech
; 16(10)2023 10 01.
Article
em En
| MEDLINE
| ID: mdl-37728477
ABSTRACT
Tissue injury-induced neutrophil recruitment is a prerequisite for the initiation and amplification of inflammatory responses. Although multiple proteases and enzymes involved in post-translational modification (PTM) of proteins regulate leukocyte recruitment, an unbiased functional screen of enzymes regulating inflammatory leukocyte recruitment has yet to be undertaken. Here, using a zebrafish tail fin amputation (TFA) model to screen a chemical library consisting of 295 compounds that target proteases and PTM enzymes, we identified multiple histone deacetylase (HDAC) inhibitors that modulate inflammatory neutrophil recruitment. AR-42, a pan-HDAC inhibitor, was shown to inhibit neutrophil recruitment in three different zebrafish sterile tissue injury models a TFA model, a copper-induced neuromast damage and mechanical otic vesicle injury (MOVI) model, and a sterile murine peritonitis model. RNA sequencing analysis of AR-42-treated fish embryos revealed downregulation of neutrophil-associated cytokines/chemokines, and exogenous supplementation with recombinant human IL-1ß and CXCL8 partially restored the defective neutrophil recruitment in AR-42-treated MOVI model fish embryos. We thus demonstrate that AR-42 non-cell-autonomously modulates neutrophil recruitment by suppressing transcriptional expression of cytokines/chemokines, thereby identifying AR-42 as a promising anti-inflammatory drug for treating sterile tissue injury-associated diseases.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peixe-Zebra
/
Inibidores de Histona Desacetilases
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article