UNASSIGNED: Despite the fact incidence and mortality vary widely among regions, sepsis remains a major cause of morbidity and cost worldwide. The importance of the endothelial barrier in sepsis and infectious diseases is increasingly recognized; however, the underlying pathophysiology of the endothelial barrier in sepsis remains poorly understood.
UNASSIGNED: Here we review the advances in basic and clinical research for relevant papers in PubMed database. We attempt to provide an updated overview of immunological alterations in endothelial dysfunction, discussing the central role of endothelial barrier involved in sepsis to provide new predictive and therapeutic paradigm for sepsis.
UNASSIGNED: Given its physiological and immunological functions in infectious diseases, the endothelial barrier has been dramatically altered in sepsis, suggesting that endothelial dysfunction may play a critical role in the pathogenesis of sepsis. Although many reliable biomarkers have been investigated to monitor endothelial activation and injury in an attempt to find diagnostic and therapeutic tools, there are no specific therapies to treat sepsis due to its complex pathophysiology. Since sepsis is initiated by both hyperinflammation and immunoparalysis occurring simultaneously, a \'one-treatment-fits-all\' strategy for sepsis-induced immune injury and immunoparalysis is bound to fail, and an individualized \'precision medicine\' approach is required.

Sepsis currently remains a major contributor to mortality in the intensive care unit (ICU), with 48.9 million cases reported globally and a mortality rate of 22.5% in 2017, accounting for almost 20% of all-cause mortality worldwide. This highlights the urgent need to improve the understanding and treatment of this condition. Sepsis is now recognized as a dysregulation of the host immune response to infection, characterized by an excessive inflammatory response and immune paralysis. This dysregulation leads to secondary infections, multiple organ dysfunction syndrome (MODS), and ultimately death. PD-L1, a co-inhibitory molecule expressed in immune cells, has emerged as a critical factor in sepsis. Numerous studies have found a significant association between the expression of PD-1/PD-L1 and sepsis, with a particular focus on PD-L1 expressed on neutrophils recently. This review explores the role of PD-1/PD-L1 in immunostimulatory and anti-inflammatory pathways, illustrates the intricate link between PD-1/PD-L1 and sepsis, and summarizes current therapeutic approaches against PD-1/PD-L1 in the treatment and prognosis of sepsis in preclinical and clinical studies.

Resistance and tolerance are two important strategies employed by the host immune response to defend against pathogens. Multidrug-resistant bacteria affect the resistance mechanisms involved in pathogen clearance. Disease tolerance, defined as the ability to reduce the negative impact of infection on the host, might be a new research direction for the treatment of infections. The lungs are highly susceptible to infections and thus are important for understanding host tolerance and its precise mechanisms. This review focuses on the factors that induce lung disease tolerance, cell and molecular mechanisms involved in tissue damage control, and the relationship between disease tolerance and sepsis immunoparalysis. Understanding the exact mechanism of lung disease tolerance could allow better assessment of the immune status of patients and provide new ideas for the treatment of infections.

Background: Sepsis is well-known to alter innate and adaptive immune responses for sustained periods after initiation by an invading pathogen. Identification of immune cell characteristics may shed light on the immune signature of patients with sepsis and further indicate the appropriate immune-modulatory therapy for distinct populations. Therefore, we aimed to establish an immune model to classify sepsis into different immune endotypes via transcriptomics data analysis of previously published cohort studies. Methods: Datasets from two observational cohort studies that included 585 consecutive sepsis patients admitted to two intensive care units were downloaded as a training cohort and an external validation cohort. We analyzed genome-wide gene expression profiles in blood from these patients by using machine learning and bioinformatics. Results: The training cohort and the validation cohort had 479 and 106 patients, respectively. Principal component analysis indicated that two immune subphenotypes associated with sepsis, designated the immunoparalysis endotype, and immunocompetent endotype, could be distinguished clearly. In the training cohort, a higher cumulative 28-day mortality was found in patients classified as having the immunoparalysis endotype, and the hazard ratio was 2.32 (95% CI: 1.53-3.46 vs. the immunocompetent endotype). External validation further demonstrated that the present model could categorize sepsis into the immunoparalysis and immunocompetent type precisely and efficiently. The percentages of 4 types of immune cells (M0 macrophages, M2 macrophages, naïve B cells, and naïve CD4 T cells) were significantly associated with 28-day cumulative mortality (P < 0.05). Conclusion: The present study developed a comprehensive tool to identify the immunoparalysis endotype and immunocompetent status in hospitalized patients with sepsis and provides novel clues for further targeting of therapeutic approaches.

UNASSIGNED: Although immune dysfunction has been investigated in adult septic patients, early immune status remains unclear. In this study, our primary aim was to assess early immune status in adult patients with sepsis stratified by age and its relevance to hospital mortality.
UNASSIGNED: A post hoc analysis of a multicenter, randomized controlled trial was conducted; 273 patients whose immune status was evaluated within 48 hours after onset of sepsis were enrolled. Early immune status was evaluated by the percentage of monocyte human leukocyte antigen-DR (mHLA-DR) in total monocytes within 48 hours after onset of sepsis and it was classified as immunoparalysis (mHLA-DR ≤30%) or non-immunoparalysis (>30%). Three logistic regression models were conducted to explore the associations between early immunoparalysis and hospital mortality. We also developed two sensitivity analyses to find out whether the definition of early immune status (24 hours vs 48 hours after onset of sepsis) and immunotherapy affect the primary outcome.
UNASSIGNED: Of the 181 elderly (≥60yrs) and 92 non-elderly (<60yrs) septic patients, 71 (39.2%) and 25 (27.2%) died in hospital, respectively. The percentage of early immunoparalysis in the elderly was twice of that in the non-elderly patients (32% vs 16%, p=0.006). For the elderly, hospital mortality was higher in the immunoparalysis ones than the non-immunoparalysis ones (53.4% vs 32.5%, p=0.009). But there was no significant difference in hospital mortality between immunoparalysis non-elderly patients and non-immunoparalysis non-elderly ones (33.5% vs 26.0%, p=0.541). By means of logistic regression models, we found that early immunoparalysis was independently associated with increased hospital mortality in elderly, but not in non-elderly patients. Sensitivity analysis further confirmed the definition of early immune status and immunotherapy did not affect the outcomes.
UNASSIGNED: The elderly were more susceptible to early immunoparalysis after onset of sepsis. Early immunoparalysis was independently associated with poor prognosis in elderly, but not in non-elderly patients.

Sepsis, the most severe manifestation of infection, poses a major challenge to health-care systems around the world. Limited ability to clean and remove the pathogen renders difficulty in septic patients to recover from the phase of immunoparalysis. The present study found the vital role of CX3CR1 internalization on sepsis-induced immunoparalysis. A mouse model with cecal ligation and puncture (CLP) and cell model with lipopolysaccharides (LPS) were employed to explore the relationship between CX3CR1 internalization and septic immunoparalysis. Immunoparalysis model in mice was established 4 days after CLP with significantly decreased proinflammatory cytokines. Flow cytometry analysis found a decreased surface expression of CX3CR1 during immunoparalysis, which was associated with reduced mRNA level and increased internalization of CX3CR1. G-protein coupled receptor kinase 2 (GRK2) and β-arrestin2 were significantly increased during septic immunoparalysis and involved in the internalization of CX3CR1. TLR4-/- or TLR4 inhibitor-treated macrophages exhibited an inhibited expression of GRK2 and β-arrestin2, along with reduced internalization of CX3CR1. Moreover, the knockdown of GRK2 and β-arrestin2 inhibited the internalization of CX3CR1 and led to a higher response on the second hit, which was associated with an increased activation of NF-κB. The critical association between internalization of CX3CR1 and immunosuppression in sepsis may provide a novel reference for clinical therapeutics.

Immunoparalysis is an important pathological mechanism in sepsis. However, an effective small molecule therapy is lacking. Here, we show that ouabain, a Na(+),K(+)-ATPase ligand, can reverse immunoparalysis in vitro, in vivo, and in clinical samples. Notably, the effect of ouabain was critically dependent on TNF-α expression. However, ouabain had opposing effects on the stability of TNF-α mRNA: Ouabain triggered miR-181 transcription, which promoted TNF-α mRNA degradation and induced immunoparalysis, and ouabain triggered the nuclear export of human antigen R (HuR), which stabilized TNF-α mRNA and suppressed immuno-paralysis. Interestingly, because the miR-181 binding site is located within the HuR binding site in the 3\'-untranslated region of TNF-α, in ouabain-treated cells, HuR competed with miR-181 for binding to TNF-α mRNA and recruited TNF-α mRNA to stress granules, thereby stabilizing TNF-α mRNA and reversing immunoparalysis. Ouabain also induced GM-CSF and interferon-γ expression in a HuR-dependent manner. Hence, the fine-tuning of TNF-α mRNA stability by HuR and miR181 plays a crucial role in immunoparalysis, and Na(+),K(+)-ATPase ligands are promising agents for immunoparalysis therapy.