A whole animal chemical screen approach to identify modifiers of intestinal neutrophilic inflammation

• Published in: The FEBS journal Vol. 284; no. 3; pp. 402 - 413
• Main Authors: Oehlers, Stefan H., Flores, Maria Vega, Hall, Christopher J., Wang, Liuyang, Ko, Dennis C., Crosier, Kathryn E., Crosier, Philip S.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.02.2017
• Subjects: Agonists; Animals; Animals, Genetically Modified; Anti-Inflammatory Agents - pharmacology; Antibiotics; chemical screen; Cholecystokinin; colitis; Colitis, Ulcerative - chemically induced; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - immunology; Colitis, Ulcerative - pathology; Crohn Disease - chemically induced; Crohn Disease - drug therapy; Crohn Disease - immunology; Crohn Disease - pathology; Danio rerio; Dextran; Dextran Sulfate; Disease Models, Animal; Dopamine; Dopamine Agonists - pharmacology; Dysbiosis - chemically induced; Dysbiosis - drug therapy; Dysbiosis - immunology; Dysbiosis - pathology; Embryo, Nonmammalian; Enterocolitis; Gene Expression; High-Throughput Screening Assays; Humans; Immunologic Factors - pharmacology; Inflammation; inflammatory bowel disease; Inflammatory bowel diseases; Intestine; Intestines - drug effects; Intestines - immunology; Intestines - pathology; Leukocytes (neutrophilic); neuro‐immune; Neutrophils - drug effects; Neutrophils - immunology; Neutrophils - pathology; Organic chemistry; Pharmacology; Receptors, Cholecystokinin - agonists; Receptors, Cholecystokinin - genetics; Receptors, Cholecystokinin - immunology; Receptors, Dopamine - genetics; Receptors, Dopamine - immunology; Rodents; Screening; Small Molecule Libraries - pharmacology; Sodium; Sodium sulfate; Sulfonic acid; Trinitrobenzenesulfonic Acid; Zebrafish; neuro-immune; colitis; inflammation; chemical screen; inflammatory bowel disease
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.13976

By performing two high‐content small molecule screens on dextran sodium sulfate‐ and trinitrobenzene sulfonic acid‐induced zebrafish enterocolitis models of inflammatory bowel disease, we have identified novel anti‐inflammatory drugs from the John Hopkins Clinical Compound Library that suppress neutrophilic inflammation. Live imaging of neutrophil distribution was used to assess the level of acute inflammation and concurrently screen for off‐target drug effects. Supporting the validity of our screening strategy, most of the anti‐inflammatory drug hits were known antibiotics or anti‐inflammatory agents. Novel hits included cholecystokinin (CCK) and dopamine receptor agonists. Using a pharmacological approach, we show that while CCK and dopamine receptor agonists alleviate enterocolitis‐associated inflammation, receptor antagonists exacerbate inflammation in zebrafish. This work highlights the utility of small molecule screening in zebrafish enterocolitis models as a tool to identify novel bioactive molecules capable of modulating acute inflammation. Inflammatory bowel disease (IBD) is a chronic condition in which neutrophils infiltrate the intestine, triggering inflammation that leads to loss of intestinal function. To identify new therapeutic avenues for intervention, Oehlers and colleagues used two zebrafish models of enterocolitis to screen the John Hopkins Clinical Compound Library for small molecules that limit neutrophilic inflammation. After validation, 23 compounds with a wide range of indications were reported to decrease neutrophil mobilization. The authors went on to show that the dopamine receptor agonist cabergoline and the cholecystokinin receptor agonist sincalide reduced neutrophilic inflammation in vivo, suggesting their potential therapeutic use in IBD.