Frontiers in immunology
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Frontiers in immunology · Jan 2020
A Peptide-Based PD1 Antagonist Enhances T-Cell Priming and Efficacy of a Prophylactic Malaria Vaccine and Promotes Survival in a Lethal Malaria Model.
The blockade of programmed cell death-1 (PD1) and its ligand PDL1 has been proven to be a successful immunotherapy against several cancers. Similar to cancer, PD1 contributes to the establishment of several chronic infectious diseases, including malaria. While monoclonal antibodies (mAbs) targeting checkpoint receptors are revolutionary in cancer treatment, the immune-related adverse events (irAEs) may prevent their utilization in prophylactic and therapeutic treatments of infectious diseases. ⋯ When combined prophylactically with an adenovirus-based or irradiated sporozoite-based malaria vaccine, LD01 significantly enhanced antigen-specific CD8+ T cell expansion. Therapeutically, LD01 treatment of mice infected with a lethal malaria strain resulted in survival that was associated with lower numbers of FOXP3+Tbet+CD4+ regulatory T cells. Taken together, our results demonstrate that LD01 is a potent immunomodulator that acts upon the adaptive immune system to stimulate T cell responses both prophylactically and therapeutically.
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Frontiers in immunology · Jan 2020
MicroRNA-200a Inhibits Inflammation and Atherosclerotic Lesion Formation by Disrupting EZH2-Mediated Methylation of STAT3.
Endothelial inflammation and dysfunction are critical to the process of atherosclerosis. Emerging evidence demonstrates that upregulation of miR-200a reduces VCAM-1 expression and prevents monocytic cell adhesion onto the aortic endothelium. However, limited information is available about the role of microRNA-200a (miR-200a) in facilitating atherosclerotic lesion formation. ⋯ EZH2 methylated STAT3 and enhanced STAT3 activity by increased tyrosine phosphorylation of STAT3, thereby increasing apoptosis and release of pro-inflammatory cytokines in ox-LDL-treated HUVECs. An anti-atherosclerotic role of miR-200a was also demonstrated in atherosclerotic mouse models. Our study demonstrates that miR-200a has anti-inflammatory and anti-atherosclerotic activities dependent on the EZH2/STAT3 signaling cascade.
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Frontiers in immunology · Jan 2020
Transcriptome Profiling of Lung Innate Immune Responses Potentially Associated With the Pathogenesis of Acinetobacter baumannii Acute Lethal Pneumonia.
Acinetobacter baumannii is one of the dominating causes of nosocomial pneumonia, however, very little is known about the host immune response associated with pathogenesis of A. baumannii infection. Here, we used a hypervirulent A. baumannii to establish an acute lethal pneumonia, supported by high bacterial burdens, severe inflammatory cells infiltration and lung damage. The lung transcriptome changes in response to A. baumannii lethal pneumonia were detected by RNA sequencing. ⋯ Immune cell typing highlighted the inflammatory response of innate immune cells headed by neutrophils. The reliability of RNA sequencing results were verified with selected differentially expressed genes by real-time PCR. This work provides an insight into the pathogenesis of lethal A. baumannii lung infection.
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Frontiers in immunology · Jan 2020
Novel Role of Endothelial Derived Exosomal HSPA12B in Regulating Macrophage Inflammatory Responses in Polymicrobial Sepsis.
Endothelial cell dysfunction contributes to sepsis induced initiate immune response and the infiltration of immune cells into organs, resulting in organ injury. Heat shock protein A12B (HSPA12B) is predominantly expressed in endothelial cells. The present study investigated whether endothelial HSPA12B could regulate macrophage pro-inflammatory response during sepsis. ⋯ Interestingly, endothelial exosomal HSPA12B significantly increases IL-10 levels and decreases TNF-α and IL-1β production in LPS-stimulated macrophages. Mechanistic studies show that endothelial exosomal HSPA12B downregulates NF-κB activation and nuclear translocation in LPS stimulated macrophages. These data suggest that endothelial HSPA12B plays a novel role in the regulation of macrophage pro-inflammatory response via exosomes during sepsis and that sepsis induced cardiomyopathy and mortality are associated with endothelial cell deficiency of HSPA12B.
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Frontiers in immunology · Jan 2020
Trib1 Contributes to Recovery From Ischemia/Reperfusion-Induced Acute Kidney Injury by Regulating the Polarization of Renal Macrophages.
Increasing evidence suggests that macrophage polarization is involved in the recovery from ischemia-reperfusion (I/R)-induced acute kidney injury (AKI), implying that the regulation of macrophage polarization homeostasis might mediate AKI recovery. Trib1 is a key regulator of macrophage differentiation, but its role in AKI remains unclear. Here, we aimed to investigate the role of Trib1 and its link with the macrophage phenotype in the process of adaptive recovery from I/R-induced renal injury. ⋯ Trib1 inhibition blocked macrophage polarization during adaptive recovery from I/R-induced moderate AKI. Our results show that Trib1 plays a role in kidney recovery and regeneration via the regulation of renal tubular cell proliferation by affecting macrophage polarization. Thus, Trib1 might be a viable therapeutic target to improve renal adaptive repair following I/R injury.