Loss of Cathepsin Z enhances pro-inflammatory macrophage responses and promotes tissue regeneration in zebrafish

The plasticity of macrophages is well documented, with fundamental roles in modulating inflammation and promoting tissue repair, notably aiming to maintain homeostasis in multicellular organisms; however, the precise factors that regulate their polarisation remain poorly understood. Cathepsin Z (ctsz) is an enzyme highly expressed in macrophages and involved in various processes, such as migration, maturation, and signal transduction, but roles in regeneration are not described. Therefore, we used zebrafish models to investigate roles of ctsz in macrophage polarisation and regeneration in the context of sterile inflammation induced by caudal fin transection. CRISPR-Cas9 mediated knockdown of ctsz led to higher pro-inflammatory tnfα+ macrophages when compared to control animals following injury (24-48 hours post-injury, hpi), as well as accelerated regenerated area. Further studies in this field could prove valuable for the development of pharmacological approaches for chronic diseases characterised by impaired tissue regeneration, such as liver fibrosis or autoimmune diseases, where dysregulated inflammation and regeneration play critical roles.