PUBLICATION
Inhibition of macrophage migration in zebrafish larvae demonstrates in vivo efficacy of human CCR2 inhibitors
- Authors
- Sommer, F., Ortiz Zacarı As, N.V., Heitman, L.H., Meijer, A.H.
- ID
- ZDB-PUB-201126-15
- Date
- 2020
- Source
- Developmental and comparative immunology 116: 103932 (Journal)
- Registered Authors
- Meijer, Annemarie H.
- Keywords
- Inhibitor, anti-inflammatory, chemokine receptor, in vivo, macrophages, screening
- MeSH Terms
-
- Animals
- Anti-Inflammatory Agents/pharmacology*
- Cell Movement/drug effects*
- Cell Movement/immunology
- Chemokine CCL2/metabolism
- Chemokine CXCL11/metabolism
- Drug Evaluation, Preclinical
- Humans
- Inflammation/metabolism
- Macrophages/drug effects*
- Macrophages/immunology
- Models, Animal
- Receptors, CCR2/antagonists & inhibitors*
- Receptors, CCR2/metabolism
- Receptors, CXCR3/metabolism
- Signal Transduction
- Zebrafish
- PubMed
- 33238180 Full text @ Dev. Comp. Immunol.
Citation
Sommer, F., Ortiz Zacarı As, N.V., Heitman, L.H., Meijer, A.H. (2020) Inhibition of macrophage migration in zebrafish larvae demonstrates in vivo efficacy of human CCR2 inhibitors. Developmental and comparative immunology. 116:103932.
Abstract
The chemokine signaling axes CCR2-CCL2 and CXCR3-CXCL11 participate in the inflammatory response by recruiting leukocytes to damaged tissue or sites of infection and are, therefore, potential pharmacological targets to treat inflammatory disorders. Although multiple CCR2 orthosteric and allosteric inhibitors have been developed, none of these compounds has been approved for clinical use, highlighting the need for a fast, simple and robust preclinical test system to determine the in vivo efficacy of CCR2 inhibitors. Herein we show that human CCL2 and CXCL11 drive macrophage recruitment in zebrafish larvae and that CCR2 inhibitors designed for humans also limit macrophage recruitment in this model organism due to the high conservation of the chemokine system. We demonstrated anti-inflammatory activities of three orthosteric and two allosteric CCR2 inhibitors using macrophage recruitment to injury as a functional read-out of their efficiency, while simultaneously evaluating toxicity. These results provide proof-of-principle for screening CCR2 inhibitors in the zebrafish model.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping