Daily Sepsis Research Analysis

The persistent challenge of sepsis-related mortality underscores the necessity for deeper insights. Our multicenter, cross-age cohort study identified insulin-like growth factor binding protein 6 (IGFBP6) as a critical regulator in sepsis diagnosis, prognosis, and mortality risk evaluation. Mechanistically, IGFBP6 engages in IGF-independent binding to prohibitin2 (PHB2) on epithelial cells, driving PHB2 tyrosine phosphorylation during sepsis. This process disrupts STAT1 phosphorylation, nuclear translocation, and its recruitment to the CCL2 promoter, ultimately impairing CCL2 transcription and macrophage chemotaxis. Crucially, PHB2 silencing via siPHB2 and STAT1 activation using 2-NP restored CCL2 expression in vitro and in vivo, improving bacterial clearance and survival in septic mice. Concurrently, IGFBP6 compromised macrophage bactericidal activity by inhibiting Akt phosphorylation, reducing ROS/IL-1β production and phagocytic capacity - defects reversible by Akt agonist SC79. Collectively, IGFBP6 emerges as an endogenous driver of sepsis pathogenesis, positioning it as a dual diagnostic biomarker and therapeutic target. Intervention strategies targeting IGFBP6-mediated signaling may offer transformative approaches for sepsis management.

Sepsis is a life-threatening disease caused by a dysfunctional host response to infection. During sepsis, inflammation-related immunosuppression is the critical factor causing secondary infection and multiple organ dysfunction syndrome. The regulatory mechanisms underlying Treg differentiation and function, which significantly contribute to septic immunosuppression, require further clarification. In this study, we found that neutrophil extracellular traps (NETs) participated in the development of sepsis-induced immunosuppression by enhancing Treg differentiation and function via direct interaction with CD4+ T cells. Briefly, NETs anchored enolase 1 (ENO1) on the membrane of CD4+ T cells through its key protein myeloperoxidase (MPO) and subsequently recruited interferon-induced transmembrane protein 2 (IFITM2). IFITM2 acted as a DNA receptor that sensed NET-DNA and activated intracellular RAS-associated protein 1B (RAP1B) and its downstream ERK signaling pathway to promote Treg differentiation and function. ENO1 inhibition significantly attenuated NET-induced Treg differentiation and alleviated sepsis in mice. Overall, we demonstrated the role of NETs in sepsis-induced immunosuppression by enhancing Treg differentiation, identified ENO1 as an anchor of NET-MPO, and elucidated the downstream molecular mechanism by which IFITM2-RAP1B-ERK regulates Treg differentiation. These findings improve our understanding of the immunopathogenesis of sepsis and provide potential therapeutic targets for sepsis-induced immunosuppression.

INTRODUCTION: Endothelial cells play a central role in the pathophysiology of sepsis-associated acute kidney injury (SA-AKI), yet we have limited understanding of the markers of microvascular-specific response. We therefore employed a translational approach integrating spatially resolved transcriptomics in a mouse SA-AKI model with validation in human kidney tissues and plasma, aiming to define the molecular signature of the endothelial response to SA-AKI in mice and in human patients. METHODS: In this post hoc analysis of prospectively collected data, we identified sepsis-associated target mRNAs and validated their expression via RT-qPCR in distinct renal microvascular compartments isolated by laser microdissection (LMD) from both cecal ligation and puncture (CLP) mice and post-mortem kidney biopsies of SA-AKI patients. Additionally, we measured the corresponding circulating proteins in plasma from two patient cohorts with sepsis and SA-AKI: one consisting of patients presenting to the emergency department, and the other of patients with severe sepsis requiring organ support in the ICU. RESULTS: We identified several differentially expressed genes in the renal microvasculature following sepsis, including Mt1, Mt2, Saa3, Hp, C3, Sparc, Mmp8, and Chil3. Whole-organ samples from CLP mice also showed increased expression in the liver and lung. Except for SPARC, all genes were similarly upregulated in human kidney biopsies from SA-AKI patients. Circulating protein levels were elevated in sepsis and SA-AKI patients compared to controls; however, only CHI3L1 and MMP8 showed significantly higher levels in SA-AKI versus sepsis across both early and advanced stages. CONCLUSION: Our findings reveal markers of the microvascular response to sepsis, which include increased levels of HP, C3, Chil3/CHI3L1, and MMP8, both at the transcriptomic level in mouse and human kidney microvasculature and at the protein level in circulating plasma of SA-AKI patients. The upregulation of these markers was shared across multiple organs and may reflect widespread endothelial activation contributing to sepsis pathophysiology.