Dechang Chen

Sepsis frequently induces intestinal barrier injury, which exacerbates systemic inflammation, and contributes to high mortality. Group 3 innate lymphoid cells (ILC3s) are key regulators of mucosal immunity, yet their role in sepsis-associated intestinal injury remains incompletely understood. We found circulating ILCPs were reduced in patients with sepsis. In an LPS-induced murine sepsis model, colonic ILC3 numbers declined whereas the residual population showed increased frequencies of IL-22- and GM-CSF-producing cells. RORγt-deficient mice exhibited impaired induction of colonic IL-22 and GM-CSF, increased intestinal permeability, and aggravated histopathological injury. Adoptive transfer of purified wild-type ILC3s restored colonic IL-22 and GM-CSF levels and partially improved barrier integrity. Mechanistically, septic ILC3s showed hypoxia-associated mitochondrial impairment and accumulation of mitochondrial ROS. increased mtROS contributed to enhanced NF-κB p65 phosphorylation and selectively supported IL-22 and GM-CSF production. Recombinant IL-22 or GM-CSF ameliorated intestinal injury. However, ROS scavenging or NF-κB inhibition increased ILC3 apoptosis, indicating that ROS-NF-κB axis also supports residual ILC3 survival. Together, these findings identify a mitochondria-associated ROS-NF-κB program that sustains protective cytokine production and survival in residual intestinal ILC3s during sepsis, although it is insufficient to prevent ongoing ILC3 loss and intestinal injury.

Critical care medicine plays a pivotal role in addressing life-threatening conditions; however, its development in China is hindered by resource scarcity a

Background: Sepsis is a global health challenge associated with high morbidity and mortality rates. Early diagnosis and treatment are challenging because of the limited understanding of its underlying mechanisms. This study aimed to identify effective biomarkers for diagnosing and treating sepsis through an integrated multi-method approach. Methods: Publicly available single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq datasets were analyzed for naive CD4 ⁺ T cell-specific genes. Based on these hub genes, Mendelian randomization (MR) analysis, followed by the MR-Bayesian model averaging (MR-BMA) algorithm, was implemented to explore the causality between these genes and sepsis. In addition, single-cell-type expression analysis, cell–cell communication detection, metabonomic evaluation, clinical samples, and both in vivo and in vitro studies were conducted to unveil the underlying mechanisms of potential therapeutic targets. Results: scRNA-seq revealed significant depletion of naive CD4 ⁺ T cells in sepsis, identifying 33 key genes. Both MR and MR-BMA analyses confirmed that elevated proportion of naive CD4 ⁺ T cell in total CD4 ⁺ T cells were related to sepsis occurrence (odds ratio [OR] = 0.90, 95% confidence interval [CI], 0.83–0.97, P = 0.007) and 28-day mortality associated with sepsis (OR = 0.75, 95% CI, 0.64–0.88, P PCED1B ) exhibited a strong causal association with 28-day mortality in patients with sepsis (OR = 0.64, 95% CI, 0.51–0.81, P PCED1B mediated the impact of proportion of naive CD4 ⁺ T cell in CD4 ⁺ T cell on sepsis-related mortality. In addition, clinical samples and both in vivo and in vitro experiments validated the elevated expression of PCED1B in naive CD4 ⁺ T cells derived from sepsis patients and mice. Mechanistic investigations revealed PCED1B ⁺ CD4 ⁺ T cells may interact with monocytes/dendritic cells through the macrophage migration inhibitory factor (MIF)–(CD74 ⁺ CD44) axis, concurrently engaging with B cells/plasmablasts through the MIF–(CD74 ⁺ CXCR4) axis, thereby regulating multiple metabolic alterations in sepsis. Conclusion: The interplay between PCED1B and naive CD4 ⁺ T cells, as revealed by this study, is instrumental in developing immunotherapeutic strategies for sepsis.