Modeling Inflammation in Zebrafish for the Development of Anti-inflammatory Drugs.

Yufei Xie,Annemarie H Meijer,Marcel J M Schaaf

doi:10.3389/fcell.2020.620984

Abstract

Dysregulation of the inflammatory response in humans can lead to various inflammatory diseases, like asthma and rheumatoid arthritis. The innate branch of the immune system, including macrophage and neutrophil functions, plays a critical role in all inflammatory diseases. This part of the immune system is well-conserved between humans and the zebrafish, which has emerged as a powerful animal model for inflammation, because it offers the possibility to image and study inflammatory responses in vivo at the early life stages. This review focuses on different inflammation models established in zebrafish, and how they are being used for the development of novel anti-inflammatory drugs. The most commonly used model is the tail fin amputation model, in which part of the tail fin of a zebrafish larva is clipped. This model has been used to study fundamental aspects of the inflammatory response, like the role of specific signaling pathways, the migration of leukocytes, and the interaction between different immune cells, and has also been used to screen libraries of natural compounds, approved drugs, and well-characterized pathway inhibitors. In other models the inflammation is induced by chemical treatment, such as lipopolysaccharide (LPS), leukotriene B4 (LTB4), and copper, and some chemical-induced models, such as treatment with trinitrobenzene sulfonic acid (TNBS), specifically model inflammation in the gastro-intestinal tract. Two mutant zebrafish lines, carrying a mutation in the hepatocyte growth factor activator inhibitor 1a gene (hai1a) and the cdp-diacylglycerolinositol 3-phosphatidyltransferase (cdipt) gene, show an inflammatory phenotype, and they provide interesting model systems for studying inflammation. These zebrafish inflammation models are often used to study the anti-inflammatory effects of glucocorticoids, to increase our understanding of the mechanism of action of this class of drugs and to develop novel glucocorticoid drugs. In this review, an overview is provided of the available inflammation models in zebrafish, and how they are used to unravel molecular mechanisms underlying the inflammatory response and to screen for novel anti-inflammatory drugs.

Highlights

Inflammation and Inflammatory DiseasesWhen the body encounters harmful stimuli, such as invading pathogens, wounding or damaged cells, the immune system will be activated and an inflammatory response is triggered (Netea et al, 2017; Chen et al, 2018)
When the body encounters harmful stimuli, such as invading pathogens, wounding or damaged cells, the immune system will be activated and an inflammatory response is triggered (Netea et al, 2017; Chen et al, 2018). This response is induced by Pattern Recognition Receptors (PRRs) such as Toll-Like Receptors (TLRs) recognizing patterns in molecules characteristic for microbes [Pathogen-Associated Molecular Patterns (PAMPs)], or molecules released by damaged cells [Damage-Associated Molecular Patterns (DAMPs)]
Since the induction of inflammation by CuSO4 can be established by just adding the compound into the culture medium, an automated high-throughput drug screening assay could be developed with this model based on leukocyte accumulation around neuromasts, using a double transgenic line with the neutrophils labeled in red and the neuromasts in green [using the claudin b promoter driving GFP expression] (d’Alençon et al, 2010; Wittmann et al, 2012)

Summary

INTRODUCTION

When the body encounters harmful stimuli, such as invading pathogens, wounding or damaged cells, the immune system will be activated and an inflammatory response is triggered (Netea et al, 2017; Chen et al, 2018). Novel inhibitors of inflammatory signaling pathways involving NF-κB, p38 MAP kinase, T lymphocyte activation, and JAK/STAT have been discovered (O’Neill, 2006; Li et al, 2017) Despite this notable progress, there is still an unmet need for more effective and safer anti-inflammatory drugs. We discuss the usefulness of the zebrafish as an animal model for studying the mechanims of inflammation and as a screening system to accerelate research aimed at the discovery of novel anti-inflammatory drugs (an overview is presented in Tables 1, 2). Genetic tools and experimental methods have been applied, leading to the successful sequencing of the zebrafish genome, enabling rapid screening of gene function, and the generation of various transgenic or mutant fish lines and models for studying human diseases (Barut and Zon, 2000; Vogel, 2000; Lieschke and Currie, 2007). Zebrafish embryos do not have cuticles, and most drugs can be delivered by adding them to the culture medium at a TABLE 1 | Overview of zebrafish models for inflammation

Introduction

CONCLUDING REMARKS