Investigating the impact of amputation (wound injury) on neuroimmune responses in zebrafish

Abstract

Macrophage infiltration into the central nervous system (CNS) is involved in many neurological disorders, in which they can play either beneficial or detrimental roles. Although infiltrating macrophages have been identified in CNS with diseases, the role of peripheral inflammatory diseases in macrophages infiltration into the brain remains unclear, especially in traumatic injuries. The present study exploited transgenic and mutant zebrafish (Danio rerio) and showed that peripheral tissue injury (tail amputation) induced macrophages/microglia infiltration into the brain accompanied by a hyperactive behavior through interleukin 1 beta (IL1β)-mediated pathways. To further explore the role of autophagy, an ancient housekeeping process, in phagocytosis and infiltration of macrophages/microglia, the use of 1-phenyl 2-thiourea (PTU), a routinely utilized inhibitor of melanogenesis, in zebrafish was first evaluated and a previously undescribed effect of PTU on autophagy in various organs and tissues of zebrafish embryos was found. Thus, a real-time tracking of autophagy and macrophages/microglia was performed in live zebrafish embryos without PTU treatment and demonstrated that autophagy is involved in macrophages/microglia phagocytosis and macrophages/microglia infiltration into the brain. Notably, unc-51-like kinase 1 (ULK1)-dependent autophagy also contributed to macrophages/microglia infiltration into the brain following peripheral tissue injury in zebrafish. These findings provided important insights into the role of pro-inflammatory cytokine and autophagy in macrophages/microglia infiltration into the brain following peripheral tissue injury, which might contribute to the development of therapeutic strategies targeting infiltrating myeloid cells in peripheral inflammatory disease-induced neurological disorders.