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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-1\u03b2 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.<\/jats:p>","DOI":"10.1242\/dmm.050056","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T13:46:16Z","timestamp":1695217576000},"source":"Crossref","is-referenced-by-count":1,"title":["Identification of histone deacetylase inhibitors as neutrophil recruitment modulators in zebrafish using a chemical library screen"],"prefix":"10.1242","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9231-7389","authenticated-orcid":false,"given":"Sijia","family":"Fan","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Chongqing Medical University 1 Laboratory of Developmental Biology, Department of Cell Biology and Genetics , , Chongqing 400016 , 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