Identification of histone deacetylase inhibitors as neutrophil recruitment modulators in zebrafish using a chemical library screen

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 enzyme...

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Bibliographic Details
Published in:Disease models & mechanisms 2023-10, Vol.16 (10)
Main Authors: Fan, Sijia, Jiang, Jinlong, Zhang, Huan, Wang, Cuihong, Kong, Shang, Zhao, Tingting, Meng, Ling, Liu, Yang, Qin, Jingjing, Rong, Xiuqin, He, Zhenting, He, Qinke, He, Ke, Chen, Ketong, Lei, Ling, Hai, Xinyu, Nie, Hong, Ren, Chunguang
Format: Article
Language:English
Subjects:
ar-42
cell migration
hdac
neutrophil
zebrafish
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Summary: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-1β 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.
ISSN:1754-8403
1754-8411
DOI:10.1242/dmm.050056