Daily Sepsis Research Analysis

Microglial pyroptosis-mediated neuroinflammation emerges as a critical pathogenic mechanism underlying sepsis-associated encephalopathy (SAE). Epigenetic modifications, especially histone acetylation states, exert fundamental regulatory effects on microglial pyroptosis. Among these, histone deacetylase 3 (HDAC3) has been identified as a central epigenetic regulator orchestrating these processes. This study investigates the functional role of HDAC3 in microglial pyroptosis and its underlying mechanisms contributing to SAE-related cognitive impairment. To explore this, male C57BL/6 mice subjected to cecal ligation and puncture (CLP) served as the SAE model. We employed RGFP966, a selective HDAC3 inhibitor, administered at 20 mg/kg/day via daily subcutaneous injections for 14 days starting 2 h prior to CLP surgery. To specifically examine HDAC3's role in microglia, we bilaterally injected recombinant adeno-associated virus (rAAV)-expressing rEGFP under the control of a DIO promoter into the hippocampus of Cx3cr1-Cre mice to achieve selective overexpression. Our data demonstrate that HDAC3 in microglia activates pyroptosis through the STING/NLRP3 pathway, exacerbating oxidative stress responses and impairing neural activity, ultimately leading to cognitive deficits in SAE. Furthermore, HDAC3 overexpression in microglia recapitulates these pathological changes, underscoring its central role in driving disease progression. Conversely, RGFP966 treatment effectively attenuates these abnormalities by suppressing HDAC3 expression and downstream inflammatory pathways. These findings highlight the therapeutic potential of targeting microglial HDAC3 to mitigate neuroinflammation and cognitive dysfunction in SAE, offering a novel direction for future clinical applications.

As a pivotal immune checkpoint molecule, programmed death-ligand 1 (PD-L1) is anchored primarily on the membrane surface of immune cells, where it exerts immunosuppressive effects, thereby facilitating tumor immune evasion. Macrophages, which serve as essential sentinels of the innate immune system, play dual regulatory roles in inflammatory pathologies, particularly during sepsis progression. While their secreted chemokines mediate inflammatory cell recruitment for pathogen clearance, excessive chemokine production can paradoxically induce organ damage and immune cell exhaustion, necessitating precise regulatory mechanisms. Conventional understanding suggests that PD-L1 on macrophages engages with programmed cell death protein 1 (PD-1) on T lymphocytes to suppress T-cell proliferation, cytokine secretion (e.g., IFN-γ and IL-2), and cytotoxic functions, thereby negatively modulating adaptive immunity. However, emerging evidence also suggests that PD-L1 has context-dependent proinflammatory functions. Given this context, we hypothesized that macrophage-intrinsic PD-L1 plays a poorly understood role in directly regulating chemokine production during sepsis. Our integrative analysis incorporating clinical database mining and RNA sequencing (RNA-seq) revealed a less defined proinflammatory property of PD-L1 under septic conditions-an ability to increase CCL8 and CXCL9 chemokine expression in inflammatory macrophages. Through combinatorial approaches, including immunoprecipitation‒mass spectrometry (IP‒MS), molecular docking, and site-directed mutagenesis, we preliminarily elucidated that PD-L1 likely governs the chemotactic mediators CCL8 and CXCL9 via the TLR4/TRAF6 signaling axis. These findings collectively establish the previously unappreciated regulatory capacity of macrophage-intrinsic PD-L1 in chemokine modulation during sepsis, potentially informing the development of innovative therapeutic strategies targeting immune dysregulation in critical care settings.

The aim of this study is to evaluate the prognostic value of the lactate to albumin ratio (LAR) in predicting morbidity, acute kidney injury associated with sepsis (SA-AKI) and mortality in sepsis patients. This was a single-center prospective cohort study. All adult patients above the age of 18 with a diagnosis of sepsis who presented between January 1, 2024, and June 1, 2025, were included. The primary outcome was 28-day mortality, septic shock and SA-AKI. The patients were divided into non-shock group and shock group, non-acute kidney injury group and acute kidney injury group, survival group and death group for comparison. Group differences were significant based on LAR quartiles. Univariate and Logistic regression analyses showed that LAR was an independent risk factor for septic shock, septic acute kidney injury, and 28-day mortality. Elevated LAR stratification was associated with a significantly increased risk of shock, acute kidney injury, and 28-day mortality. LAR remained an independent risk factor for shock, acute kidney injury, and death when used as a continuous variable. Receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) of septic shock was 0.705 (95% CI = 0.611-0.800) when the cutoff value of LAR was 0.106. When the cutoff value was 0.097, the AUC of sepsis-induced acute kidney injury was 0.762 (95% CI = 0.669-0.854). When the cutoff value was 0.098, the AUC of 28-day mortality was 0.863 (95% CI = 0.796-0.931). As the quartile of LAR layers increases, the risks of septic shock, SA-AKI and death gradually increased significantly. Early LAR has a certain predictive value for septic shock, SA-AKI and death outcomes.