Molecular Actors of Inflammation and Their Signaling Pathways: Mechanistic Insights from Zebrafish

SIMPLE SUMMARY: Inflammation is a central part of the body’s response to harm that can be elicited by microbes, environmental factors, or internal injuries. This complex physiological process has evolved to protect the body and eliminate the threat. To do so, it relies on immune cells and molecular mediators that act in concert to provide protection and tissue repair. If return to homeostasis fails, prolonged inflammation can cause tissue damage and chronic diseases. It is therefore essential to understand in detail the mechanisms at play during the inflammatory response, in order to modulate them in a pathological context. Such studies strongly benefit from in vivo models, as these can capture the complexity of inflammation as a whole. Zebrafish has proven to be a valuable animal model to study innate immune responses as its immune system shows high similarity with the human one and it offers numerous advantages such as its genetics and transparency. We here review the current knowledge on the molecular actors of inflammation in zebrafish, highlighting how the tools developed to study them have helped gain insights into the mechanisms of inflammation. This will allow to design more refined models of inflammation, mimicking human diseases, for drug screening in zebrafish. ABSTRACT: Inflammation is a hallmark of the physiological response to aggressions. It is orchestrated by a plethora of molecules that detect the danger, signal intracellularly, and activate immune mechanisms to fight the threat. Understanding these processes at a level that allows to modulate their fate in a pathological context strongly relies on in vivo studies, as these can capture the complexity of the whole process and integrate the intricate interplay between the cellular and molecular actors of inflammation. Over the years, zebrafish has proven to be a well-recognized model to study immune responses linked to human physiopathology. We here provide a systematic review of the molecular effectors of inflammation known in this vertebrate and recapitulate their modes of action, as inferred from sterile or infection-based inflammatory models. We present a comprehensive analysis of their sequence, expression, and tissue distribution and summarize the tools that have been developed to study their function. We further highlight how these tools helped gain insights into the mechanisms of immune cell activation, induction, or resolution of inflammation, by uncovering downstream receptors and signaling pathways. These progresses pave the way for more refined models of inflammation, mimicking human diseases and enabling drug development using zebrafish models.