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Endothelial-Derived Interleukin-1? Activates Innate Immunity by Promoting the Bactericidal Activity of Transendothelial Neutrophils.

ABSTRACT: Migration of neutrophils across endothelial barriers to capture and eliminate bacteria is served as the first line of innate immunity. Bacterial virulence factors damage endothelium to produce inflammatory cytokines interacts with neutrophils. However, the mechanisms that behind endothelial-neutrophil interaction impact on the bactericidal activity remain unclear. Therefore, we aimed to find the target proteins on endothelial cells that triggered the bactericidal activity of transendothelial neutrophils. Herein, we built the infected models on rats and endothelial-neutrophil co-cultural system (Transwell) and discovered that endothelial-derived IL-1? promoted the survival of rats under Escherichia coli infection and enhanced the bactericidal activity of transendothelial neutrophils in vivo and in vitro. Results further showed that IL-1? was inhibited by lipopolysaccharide (LPS) in the endothelial-neutrophil interaction. We found that LPS mainly damaged cell membrane and induced cell necrosis to interrupt neutrophil migration from endothelial barrier. Thus, we used the isobaric tags for relative and absolute quantification (iTRAQ) method to identify different proteins of endothelial cells. Results showed that IL-1? targeted cellular plasma membrane, endoplasmic reticulum and mitochondrial envelope and triggered eleven common proteins to persistently regulate. During the early phase, IL-1? triggered the upregulation of cell adhesion molecules (CAMs) to promote neutrophil adhesion, while oxidative phosphorylation was involved in long time regulation to induce transmigration of neutrophils against bacteria. Our results highlight the critical mechanism of endothelial-derived IL-1? on promoting bactericidal activity of transendothelial neutrophils and the findings of IL-1? triggered proteins provide the potentially important targets on the regulation of innate immunity.

SUBMITTER: Liu X

PROVIDER: S-EPMC7358461 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Endothelial-Derived Interleukin-1α Activates Innate Immunity by Promoting the Bactericidal Activity of Transendothelial Neutrophils.

Liu Xiaoye X Zhang Hui H He Shangwen S Mu Xiang X Hu Ge G Dong Hong H

Frontiers in cell and developmental biology 20200707

Migration of neutrophils across endothelial barriers to capture and eliminate bacteria is served as the first line of innate immunity. Bacterial virulence factors damage endothelium to produce inflammatory cytokines interacts with neutrophils. However, the mechanisms that behind endothelial-neutrophil interaction impact on the bactericidal activity remain unclear. Therefore, we aimed to find the target proteins on endothelial cells that triggered the bactericidal activity of transendothelial neu ...[more]

PMID: 32733891

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Project description:Discrimination between self vs. non-self and adequate response to infection and tissue damage are fundamental functions of the immune system. The rapid and global spread of known and emerging viruses is a testament that the timely detection of viral pathogens that reproduce within host cells, presents a formidable challenge to the immune system. To gain access to a proper reproductive niche, many pathogens travel via the host vasculature and therefore become exposed to humoral factors of the innate immune system. Although a cascade of coagulation factors plays a fundamental role in host defense for “living fossils” such as horseshoe crabs (Xiphosurida spp), the role of the coagulation system in activation of innate responses to pathogens in higher organisms remains unclear. When human type C adenovirus (HAdv) enters the circulation, 240 copies of coagulation factor X (FX) bind to the virus particle with picomolar affinity. Here, using molecular dynamics flexible fitting (MDFF) and high resolution cryo-electron microscopy (cryo-EM), we defined the interface between the HAdv5 hexon protein and FX at pseudo-atomic level. Based on this structural data, we introduced a single amino acid substitution, T424A, in the hexon that completely abrogated FX interaction with the virus. In vivo genome-wide transcriptional profiling revealed that FX-binding-ablated virus failed to activate a distinct network of the early response genes, whose expression depends on transcription factor NFKB1. Deconvolution of the signaling network responsible for early gene activation showed that the FX-HAdv complex triggers MyD88/TRIF/TRAF6 signaling upon activation of toll-like receptor 4 (TLR4) that serves as a principal sensor of FX-virus complex in vivo. Our study implicates host factor “decoration” of the virus as a mechanism to trigger innate immune sensor that respond to a misplacement of coagulation FX from the blood into intracellular macrophage compartments upon virus entry into the cell. Our results further the mounting evidence of evolutionary conservation between the coagulation system and innate immunity. Two strains of mice, C57BL/6, and Il1r1-/- deficient. Mice were challenged with wild type HAdv5 or HAdv5-based vectors.

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Endothelial-Derived Interleukin-1? Activates Innate Immunity by Promoting the Bactericidal Activity of Transendothelial Neutrophils.

Publications

Endothelial-Derived Interleukin-1α Activates Innate Immunity by Promoting the Bactericidal Activity of Transendothelial Neutrophils.

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