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[Display omitted] • DEX promotes inflammation resolving. • DEX increases the protein levels of TGF-β1. • DEX up-regulates the CD11b+F4/80+Ly6G+ population ratio. • DEX enhances resolution of inflammation via TGF-β1. Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist, which can regulate inflammatory responses. However, whether DEX interferes with the inflammation resolving remains unclear. Here, we reported the effects of DEX on zymosan-induced generalized inflammation in mice during resolution. Mice were administered intraperitoneally with DEX after the initiation of sepsis. The resolution interval (Ri), a vital resolution indice, decreased from twelve hours to eight hours after the administration of DEX. The induction of peritoneal pro-inflammatory interleukin [IL] - 1β and tumour necrosis factor-α (TNF-α) appeared to be inhibited. Of interest, the anti-inflammatory transforming growth factor-β1 (TGF-β1) but not IL-10 levels were up-regulated at twenty-four hours in the DEX group along with 1.0 mg/mice zymosan A (ZyA) treatment. The expression levels of multiple genes related to protective immune processes and clearance functions were detected and revealed the same trends. DEX markedly increased the F4/80+Ly6G+ macrophage population. Additionally, the adequate apoptotic neutrophil clearance from injury after DEX installation could be reverse by opsonization or co-instillation of TGF-β1 neutralizing antibody in vivo, promoting the inflammation-resolution programs. In conclusion, DEX post-treatment, via the increase of F4/80+Ly6G+ macrophages, provokes further secretion of TGF-β1, leading to the attenuated cytokine storm and accelerated inflammation resolving. [ABSTRACT FROM AUTHOR]

Background: Circulating extracellular vesicles (EVs) are recognized as a promising source of cancer biomarkers. We previously reported that tumor cell-released autophagosomes, a new subgroup of EVs expressing the mature autophagosome-specific marker LC3B (LC3B + EVs), are critical modulators of host anti-tumor immunity. This study aimed to assess the level of plasma LC3B + EVs and the correlation with clinical outcomes in liver cancer patients., Methods: The plasma and ascites samples were obtained from patients with liver cancer, non-malignant liver disease, and healthy controls. EVs were isolated by differential centrifugation and characterized using flow cytometry, nanoparticle tracking analysis, transmission electron microscopy, and western blotting. Receiver operating characteristic curve (ROC) was used to evaluate the diagnostic efficacy of plasma LC3B + EVs or HSP90α + LC3B + EVs from liver cancer patients. The relationship between the expression levels of HSP90AA1 or MAP1LC3B and survival were analyzed using patient data from the TCGA database. The correlation between HSP90α in LC3B + EVs and PD-1 high CD8 + exhausted T cells from the ascites and peripheral blood of liver cancer patients was also evaluated., Results: The EVs preparation from liver cancer patients contained LC3B + EVs expressing epithelial tumor cell adhesion molecules (EpCAM), indicating that these LC3B + EVs originated from epithelial tumor cells. The levels of plasma LC3B + EVs and HSP90α + LC3B + EVs in liver cancer patients were significantly higher than in non-malignant liver disease patients and healthy controls. The expression of HSP90α in plasma LC3B + EVs (AUC 0.9595, sensitivity 86.00%, specificity 96.67%) accurately differentiated liver cancer patients from non-liver cancer controls. Additionally, a significant decrease in the levels of plasma LC3B + EVs and HSP90α + LC3B + EVs was found post-surgery in each patient, and high expression of HSP90AA1 or MAP1LC3B in the tumor tissue correlated with significantly worse survival compared to those with low expression. We also observed that the level of LC3B + EVs and HSP90α + LC3B + EVs positively correlated with the PD-1 high CD8 + exhausted T cells in liver cancer patients. Human CD8 + T cells treated with purified LC3B + EVs in vitro exhibited a dose-dependent increase in the percentage of PD-1 + CD8 + T cells, whereas the production of IFN-γ was decreased., Conclusions: We demonstrated that isolation and detection of plasma LC3B + EVs carrying bioactive molecules is an effective diagnostic marker of liver cancer, and may also be used as a potential marker for immune monitoring and predicting prognosis clinically., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

The formation of an immunosuppressive microenvironment and up-regulation of PD-L1 protein are the main causes of tumor immune escape. Previous reports suggest that Angiotensin II (Ang II) can modulate the immune status of tumor microenvironment in non-small cell lung cancer (NSCLC), but the underlying mechanism remains not fully understood. Here we demonstrated that AngII treatment causes the reduction of intratumoral infiltrating CD4 T lymphocytes in tumor-bearing mice, increases the accumulation of immunosuppressive granulocytes and TAMs in tumor tissue, and upregulates the expression levels of immunosuppressive marker genes. In addition, AngII/AGTR1 axis triggers cell PD-L1 expression through a mechanism involving increases in PD-L1 mRNA stability by human antigen R (HuR), an AU-rich element (ARE)-binding protein. Collectively, AngII/AGTR1 signaling promotes the tumor immunosuppressive microenvironment by upregulating PD-L1 in NSCLC, the mechanism of which is largely accounted by HuR-mediated PD-L1 mRNA stabilization., (Copyright © 2020 Elsevier B.V. All rights reserved.)