Despite well-known systemic immune reactions in peripheral trauma, little is known about their roles in posttraumatic neurological disorders, such as anxiety, sickness, and cognitive impairment. Leukocyte invasion of the brain, a common denominator of systemic inflammation, is involved in neurological disorders that occur in peripheral inflammatory diseases, whereas the influences of peripheral leukocytes on the brain after peripheral trauma remain largely unclear. In this study, we found that leukocytes, largely macrophages, transiently invaded the brain of zebrafish larvae after peripheral trauma through vasculature-independent migration, which was a part of the systemic inflammation and was mediated by interleukin-1b (il1b). Notably, myeloid cells in the brain that consist of microglia and invading macrophages were implicated in posttraumatic anxiety-like behaviors, such as hyperactivity (restlessness) and thigmotaxis (avoidance), while a reduction in systemic inflammation or myeloid cells can rescue these behaviors. In addition, invading leukocytes together with microglia were found to be responsible for the clearance of apoptotic cells in the brain; however, they also removed the nonapoptotic cells, which suggested that phagocytes have dual roles in the brain after peripheral trauma. More importantly, a category of conserved proteins between zebrafish and humans or rodents that has been featured in systemic inflammation and neurological disorders was determined in the zebrafish brain after peripheral trauma, which supported that zebrafish is a translational model of posttraumatic neurological disorders. These findings depicted leukocyte invasion of the brain during systemic inflammation after peripheral trauma and its influences on the brain through il1b-dependent mechanisms.
Despite the well-described discrepancy between some of the macroautophagy/autophagy-related genes (ATGs) in the regulation of hematopoiesis, the varying essentiality of core ATGs in vertebrate definitive hematopoiesis remains largely unclear. Here, we employed zebrafish (Danio rerio) to compare the function of six core atgs from the core autophagy machineries, which included atg13, beclin1 (becn1), atg9a, atg2a, atg5, and atg3, in vertebrate definitive hematopoiesis via CRISPR-Cas9 ribonucleoprotein targeting. Zebrafish embryos with various atg mutations showed autophagic deficiency throughout the body, including hematopoietic cells. The atgs mutations unsurprisingly caused distinctive hematopoietic abnormalities in zebrafish. Notably, becn1 or atg9a mutation resulted in hematopoietic stem cells (HSCs) expansion during the development of the embryo into a larva, which can be attributed to the proteomic changes in metabolism, HSCs regulators, and apoptosis. Besides, atg3 mutation lowered the leukocytes in developing zebrafish embryos. Intriguingly, a synergistic effect on HSCs expansion was identified in atg13+becn1 and atg9a+atg2a or atg3 double mutations, in which atg13 mutation and atg2a or atg3 mutation exacerbated and mitigated the HSCs expansion in becn1 and atg9a mutations, respectively. In addition, the myeloid cell type-specific effects of various atgs were also determined between neutrophils and macrophages. Of these, a skewed ratio of neutrophils versus macrophages was found in atg13 mutation, while both of them were reduced in atg3 mutation. These findings demonstrated the distinct roles of atgs and their interplays in zebrafish definitive hematopoiesis, thereby suggested that the vertebrate definitive hematopoiesis is regulated in an atgs-dependent manner.
PTEN-induced putative kinase 1 (PINK1) is a well-characterized regulator of mitochondrial quality control through mitophagy and its mutations are associated with recessive Parkinson’s disease. However, little is known about its functions in normal and malignant hematopoiesis in vertebrates. Here we aim to unravel the roles of PINK1 in definitive hematopoiesis and its underlying mechanisms using zebrafish (Danio rerio). In this study, we utilized CRISPR/Cas9 system to generate pink1 knockout zebrafish model and PINK1-deficient leukemia cell line. We found that pink1 deficiency activated autophagy in hematopoietic cells and promoted definitive hematopoiesis in zebrafish embryos, which can be alleviated by canonical autophagy inhibition. Further, the proteomic and metabolic analysis revealed an elevated expression of cell proliferation markers and enhanced respiration in pink1-deficient zebrafish embryos. On the other hand, PINK1 deficiency also induced autophagy and cell proliferation in human leukemic cells. Therefore, our findings demonstrated that PINK1 functions as a negative regulator of normal and malignant hematopoiesis through the autophagy-mediated pathway.
Background: Infiltration of macrophages into the central nervous system (CNS) is involved in many neurological disorders, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and autism. Despite extensive studies into neuroinflammation associated macrophage infiltration into the CNS, its underlying mechanisms and pathological roles remain unclear, especially when triggered by peripheral inflammation. Methods: To further elucidate the role and mechanism of peripheral inflammation in neurological disorders, we exploited interleukin 1 beta (il1b) mutant transgenic zebrafish (Danio rerio) with fluorescent protein expression restricted to macrophages to track the macrophage migration under peripheral inflammation following tail amputation.Results: We found that macrophage infiltration into the brain of zebrafish embryo following peripheral tissue injury can be alleviated via genetically targeting il1b. In addition, through circulation-independent migration, macrophages infiltrate brains with evidence of increased apoptosis. We further identified the expression of camk2g1 in the brains of zebrafish with hyperactive behavior following peripheral tissue injury. This il1b-regulated protein is associated with neuropsychiatry disorders. Conclusion: These findings demonstrated that peripheral tissue injury induces il1b-mediated macrophage infiltration into the brain and a hyperactive behavior.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.