GENERATION OF TOLEROGENIC DENDRITIC CELLS UNDER THE PERSISTENT INFLAMMATION STIMULATION.

ABSTRACT: Immunosuppression, commonly accompanied by persistent inflammation, is a key feature in the later phase of sepsis. However, the pathophysiological mechanisms underlying this phenomenon remain unclear. Dendritic cells (DCs), specifically tolerogenic DCs (tolDCs), play a crucial role in this process by regulating immune responses through inducing T cell anergy and releasing anti-inflammatory cytokines. Nevertheless, the existing cell models are inadequate for investigating tolDCs during the immunosuppressive phase of sepsis. Therefore, this study aimed to develop a novel in vitro model to generate tolDCs under chronic inflammatory conditions. We have successfully generated tolDCs by exposing them to sublethal lipopolysaccharide (LPS) for 72 h while preserving cell viability. Considering that IL-10-induced tolDCs (IL-10-tolDCs) are well-established models, we compared the immunological tolerance between LPS-tolDCs and IL-10-tolDCs. Our findings indicated that both LPS-tolDCs and IL-10-tolDCs exhibited reduced expression of maturation markers, whereas their levels of inhibitory markers were elevated. Furthermore, the immunoregulatory activities of LPS-tolDCs and IL-10-tolDCs were found to be comparable. These dysfunctions include impaired antigen presenting capacity and suppression of T cell activation, proliferation, and differentiation. Notably, compared with IL-10-tolDCs, LPS-tolDCs showed a reduced response in maturation and cytokine production upon stimulation, indicating their potential as a better model for research. Overall, in comparison with IL-10-tolDCs, our data suggest that the immunological dysfunctions shown in LPS-tolDCs could more effectively elucidate the increased susceptibility to secondary infections during sepsis. Consequently, LPS-tolDCs have emerged as promising therapeutic targets for ameliorating the immunosuppressed state in septic patients.

Clinical practice of sepsis-induced immunosuppression: Current immunotherapy and future options.

Sepsis is a potentially fatal condition characterized by the failure of one or more organs due to a disordered host response to infection. The development of sepsis is closely linked to immune dysfunction. As a result, immunotherapy has gained traction as a promising approach to sepsis treatment, as it holds the potential to reverse immunosuppression and restore immune balance, thereby improving the prognosis of septic patients. However, due to the highly heterogeneous nature of sepsis, it is crucial to carefully select the appropriate patient population for immunotherapy. This review summarizes the current and evolved treatments for sepsis-induced immunosuppression to enhance clinicians' understanding and practical application of immunotherapy in the management of sepsis.

Dynamic increase in myoglobin level is associated with poor prognosis in critically ill patients: a retrospective cohort study.

Background: Myoglobin is an important biomarker for monitoring critically ill patients. However, the relationship between its dynamic changes and prognosis remains unclear. Methods: We retrospectively enrolled 11,218 critically ill patients from a general and surgical intensive care unit (ICU) of a tertiary hospital between June 2016 and May 2020. Patients with acute cardiovascular events, cardiac and major vascular surgeries, and rhabdomyolysis were excluded. To investigate the early myoglobin distribution, the critically ill patients were stratified according to the highest myoglobin level within 48 h after ICU admission. Based on this, the critically ill patients with more than three measurements within 1 week after ICU admission were included, and latent class trajectory modeling was used to classify the patients. The characteristics and outcomes were compared among groups. Sensitivity analysis was performed to exclude patients who had died within 72 h after ICU admission. Restricted mean survival time regression model based on pseudo values was used to determine the 28-day relative changes in survival time among latent classes. The primary outcome was evaluated with comparison of in-hospital mortality among each Trajectory group, and the secondary outcome was 28-day mortality. Results: Of 6,872 critically ill patients, 3,886 (56.5%) had an elevated myoglobin level (≥150 ng/mL) at admission to ICU, and the in-hospital mortality significantly increased when myoglobin level exceeded 1,000 µg/mL. In LCTM, 2,448 patients were unsupervisedly divided into four groups, including the steady group (n = 1,606, 65.6%), the gradually decreasing group (n = 523, 21.4%), the slowly rising group (n = 272, 11.1%), and the rapidly rising group (n = 47, 1.9%). The rapidly rising group had the largest proportion of sepsis (59.6%), the highest median Sequential Organ Failure Assessment (SOFA) score (10), and the highest in-hospital mortality (74.5%). Sensitivity analysis confirmed that 98.2% of the patients were classified into the same group as in the original model. Compared with the steady group, the rapidly rising group and the slowly rising group were significantly related to the reduction in 28-day survival time (ß = -12.08; 95% CI -15.30 to -8.86; ß = -4.25, 95% CI -5.54 to -2.97, respectively). Conclusion: Elevated myoglobin level is common in critically ill patients admitted to the ICU. Dynamic monitoring of myoglobin levels offers benefit for the prognosis assessment of critically ill patients.

DIAPH1 regulates chromosomal instability of cancer cells by controlling microtubule dynamics.

Chromosomal instability (CIN) is a hallmark of cancer, resulting from misalignment and missegregation of chromosomes during meta- and anaphase, due to non-precise regulation of spindle-MT dynamics. Diaphanous Related Formin 1 (DIAPH1) is an actin nucleator and also binds microtubule (MT) with high affinity. In this study, we analyzed the role of DIAPH1 in regulation of spindle MT-dynamics and CIN in HT29 and HCT-116 colorectal cancer (CRC) cells. Our data show that down-regulation of DIAPH1 in these cell lines decreased spindle-MT speed by 50 % and the fraction of cells with misaligned and missegregated chromosomes was significantly increased. Furthermore, in HCT-116 DIAPH1 depleted cells deviation of chromosome number was elevated and the number of cells with micronuclei and cytosolic DNA was increased in both DIAPH1-knock down cell lines. In line with these results, database analysis revealed a significant correlation with low DIAPH1 mRNA expression and aneuploidy. Thus, DIAPH1 is substantially involved in the control of CIN in CRC cells. Since in vitro, DIAPH1 directly increased MT-polymerization, we assume that DIAPH1 controls CIN by regulating spindle-MT dynamics.