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

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 polarization remain poorly understood. Cathepsin Z (CTSZ) encodes an enzyme highly expressed in macrophages and involved in various processes, such as migration, maturation and signal transduction, but its roles in regeneration are not described. Therefore, we used zebrafish models to investigate the roles of ctsz in macrophage polarization 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 than in control animals following injury (24-48 h post-injury), as well as accelerated regenerated area. Further studies in this field could prove valuable for the development of pharmacological approaches for chronic diseases characterized by impaired tissue regeneration, such as liver fibrosis or autoimmune diseases, in which dysregulated inflammation and regeneration play critical roles.