Abstract
Endotoxemia is a condition in which endotoxins enter the blood stream and cause systemic and sometimes lethal inflammation. Zebra fish provides a genetically tractable model organism for studying innate immunity, with additional advantages in live imaging and drug discovery. However, a bona fide endotoxemia model has not been established in zebra fish. Here, we have developed an acute endotoxemia model in zebra fish by injecting a single dose of LPS directly into the circulation. Hallmarks of human acute endotoxemia, including systemic inflammation, extensive tissue damage, circulation blockade, immune cell mobilization, and emergency hematopoiesis, were recapitulated in this model. Knocking out the adaptor protein Myd88 inhibited systemic inflammation and improved zebra fish survival. In addition, similar alternations of pathways with human acute endotoxemia were detected using global proteomic profiling and MetaCore™ pathway enrichment analysis. Furthermore, treating zebra fish with a protein tyrosine phosphatase nonreceptor type 11 (Shp2) inhibitor decreased systemic inflammation, immune mobilization, tissue damage, and improved survival in the endotoxemia model. Together, we have established and characterized the phenotypic and gene expression changes of a zebra fish endotoxemia model, which is amenable to genetic and pharmacological discoveries that can ultimately lead to a better mechanistic understanding of the dynamics and interplay of the innate immune system.
Highlights
The clinical manifestations associated with Gram-negative bacterial infection, such as vascular damage and leakage, disseminated intravascular coagulation, tissue hypoxia, systemic inflammation, cytokine storm, and in extreme cases elevation into sepsis [1, 2], are often caused by the presence of bacteria cell wall contents
We report a zebra fish endotoxemia model facilitated by IV injection of LPS into 3 dpf larvae
Results were normalized with ef1α and are presented as means ± SD (n = 3 biological repeats with 20 larvae in each group). *p < 0.05, **p < 0.01, ****p < 0.0001, Sidak’s multiple comparisons test. (E,F) Tg(βactin:secANV-YFP)pu17 were treated with DMSO or 11a-1 and injected with LPS
Summary
The clinical manifestations associated with Gram-negative bacterial infection, such as vascular damage and leakage, disseminated intravascular coagulation, tissue hypoxia, systemic inflammation, cytokine storm, and in extreme cases elevation into sepsis [1, 2], are often caused by the presence of bacteria cell wall contents. Among these components are endotoxins or lipopolysaccharides (LPS) [3], which enter the blood circulation [4]. There is a need to develop other animal models that can complement the cell culture and murine models
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