Daily Sepsis Research Analysis
Three mechanistic and translational studies reshape our understanding of sepsis: a Nature Communications paper uncovers a gut–brain immune axis driving sepsis-associated encephalopathy via γδ T17 cells and STING/C1q-dependent microglial pruning; an Advanced Science study reveals an IL1R2–ENO1 interaction that restrains glycolysis-driven pyroptosis, improving survival in murine sepsis; and a multi-cohort meta-analysis identifies conserved severity-associated myeloid programs (emergency myelopoies
Summary
Three mechanistic and translational studies reshape our understanding of sepsis: a Nature Communications paper uncovers a gut–brain immune axis driving sepsis-associated encephalopathy via γδ T17 cells and STING/C1q-dependent microglial pruning; an Advanced Science study reveals an IL1R2–ENO1 interaction that restrains glycolysis-driven pyroptosis, improving survival in murine sepsis; and a multi-cohort meta-analysis identifies conserved severity-associated myeloid programs (emergency myelopoiesis, IL1R2-high states) across bacterial and viral infections.
Research Themes
- Gut–brain immune axis in sepsis-associated encephalopathy
- Immunometabolism and pyroptosis regulation via IL1R2–ENO1
- Conserved severity-associated myeloid programs across infections
Selected Articles
1. Small intestinal γδ T17 cells promote SAE through STING/C1q-induced microglial synaptic pruning in male mice.
This study shows that IL-7R+ γδ T17 cells originating from the small intestine migrate to the brain after sepsis and trigger microglial synaptic pruning via STING/C1q signaling, driving sepsis-associated encephalopathy. The work establishes a gut–brain immune axis in sepsis with sex-specific evidence in male mice and identifies actionable nodes (STING, C1q, γδ T17 trafficking).
Impact: Reveals a previously unrecognized gut–brain immune pathway in sepsis that directly links intestinal γδ T17 responses to neuroinflammation and synaptic dysfunction. This opens therapeutic avenues to prevent or treat sepsis-associated encephalopathy.
Clinical Implications: Suggests potential for targeting STING/C1q signaling or γδ T17 cell trafficking to mitigate sepsis-associated encephalopathy. Highlights the need to consider gut immune modulation in neuroprotective strategies post-sepsis.
Key Findings
- Sepsis induces migration of small intestinal IL-7R+ γδ T17 cells to the brain.
- γδ T17 cells drive microglial synaptic pruning through STING/C1q signaling.
- Mechanism establishes a gut–brain immune axis underlying sepsis-associated encephalopathy in male mice.
Methodological Strengths
- In vivo mechanistic dissection linking gut lymphocyte migration to brain microglial function
- Identification of specific signaling (STING/C1q) enabling actionable targeting
Limitations
- Sex-specific findings presented in male mice; generalizability across sexes/species requires validation
- Translational evidence in human sepsis is not yet provided
Future Directions: Test STING/C1q blockade and γδ T17 trafficking inhibitors in sepsis models including females; validate γδ T17 signatures and neuroimaging correlates in human sepsis-associated encephalopathy.
Sepsis is a severe global health issue with high mortality rates, and sepsis-associated encephalopathy (SAE) further exacerbates this risk. While recent studies have shown the migration of gut immune cells to the lungs after sepsis, their impact on the central nervous system remains unclear. Our research demonstrates that sepsis could induce the migration of IL-7R
2. Critical Role of IL1R2-ENO1 Interaction in Inhibiting Glycolysis-Mediated Pyroptosis for Protection Against Lethal Sepsis.
The authors identify ENO1 as a binding partner of IL1R2 in macrophages, showing that IL1R2 suppresses ENO1 activity to curb glycolysis, GSDMD-mediated pyroptosis, and inflammation. IL1R2-deficient mice fare worse in sepsis, while ENO1 inhibition improves survival, positioning the IL1R2–ENO1 axis as a therapeutic checkpoint in immunometabolism.
Impact: Defines a novel metabolic mechanism linking IL1R2 to glycolysis and pyroptosis, with direct survival benefit in murine sepsis through ENO1 inhibition. It advances druggable targets at the interface of inflammation and metabolism.
Clinical Implications: Therapeutic targeting of the IL1R2–ENO1 interaction or ENO1 activity may reduce pyroptosis and organ injury in sepsis. sIL1R2 dynamics could serve as a biomarker to stratify patients for immunometabolic interventions.
Key Findings
- sIL1R2 is elevated in septic patients and mice; intracellular IL1R2 decreases during macrophage pyroptosis.
- Proteomics identifies ENO1 as an IL1R2-binding partner; IL1R2 suppresses ENO1 to inhibit glycolysis and GSDMD-mediated pyroptosis.
- IL1R2-deficient mice have worse sepsis outcomes; ENO1 inhibition reduces inflammation, organ injury, and improves survival.
Methodological Strengths
- Multi-system validation including human samples, proteomics, and genetic mouse models
- Clear mechanistic link between IL1R2–ENO1 interaction and pyroptosis with survival readouts
Limitations
- Human cohort size and clinical correlates are not detailed; translational pathways need formal trials
- Potential off-target effects and safety of ENO1 inhibition remain to be established
Future Directions: Develop small molecules/biologics that modulate IL1R2–ENO1; evaluate sIL1R2 as a stratification biomarker; test efficacy in larger animal models and early-phase sepsis trials.
Immune cell metabolic reprogramming toward glycolysis is vital for sepsis defense. While interleukin 1 receptor 2 (IL1R2) acts as a decoy receptor for IL1α/β, its potential impact on cell metabolism and death during sepsis remains unclear. This study observed elevated plasma soluble IL1R2 (sIL1R2) levels in septic patients and mice. In pyroptotic macrophages, reduced intracellular IL1R2 expression led to its release extracellularly. Proteomic screening identified enolase 1 (ENO1), a key glycolysis enzyme, as the binding partner of IL1R2 in macrophages. IL1R2 suppresses ENO1 activity to inhibit glycolysis, gasdermin D (GSDMD)-mediated pyroptosis, and inflammation in macrophages. IL1R2-deficient mice exhibited heightened susceptibility to sepsis, with increased inflammation, organ injury, and mortality. Notably, ENO1 inhibition reduced inflammation, organ injury, and improved survival rates in septic mice. The study reveals that IL1R2 interacts with ENO1 to inhibit glycolysis-mediated pyroptosis and inflammation in sepsis, suggesting the IL1R2-ENO1 interaction as a promising therapeutic target of sepsis.
3. Systemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infections.
A meta-analysis across 1845 patients identifies a conserved severity-associated myeloid program characterized by emergency myelopoiesis and IL1R2-high monocytes/neutrophils in bacterial sepsis, COVID-19, and influenza. IL-6 blockade partially attenuates this signature with compensatory G-CSF increases, and mouse influenza models corroborate cytokine-driven induction.
Impact: Provides a unifying endotype of severe infection across pathogens, linking systemic cytokines to myeloid state transitions and suggesting testable targets (IL-6, G-CSF axis) for modulating detrimental myelopoiesis.
Clinical Implications: Supports biomarker development using IL1R2-high myeloid signatures and informs cytokine-modulating strategies (e.g., IL-6 blockade with attention to G-CSF feedback) in severe infections, including sepsis.
Key Findings
- Meta-analysis of 1845 patients across 25 studies reveals a conserved severity-associated myeloid signature (emergency myelopoiesis and IL1R2-high monocytes/neutrophils) in sepsis, COVID-19, and influenza.
- In tocilizumab-treated COVID-19 patients, IL-6 blockade partially reduces this signature but increases G-CSF, indicating compensatory cytokine responses.
- Mouse influenza models validate cytokine-driven induction of IL1R2+ myeloid cells, supporting causality.
Methodological Strengths
- Large multi-cohort integration with both single-cell and bulk transcriptomics
- Human interventional perturbation analysis (tocilizumab) plus in vivo validation
Limitations
- Heterogeneity across cohorts and pathogens; observational nature limits causal inference in humans
- Partial reversal with IL-6 blockade suggests network redundancy; optimal therapeutic combination remains unclear
Future Directions: Prospective validation of IL1R2-high myeloid biomarkers in sepsis; trial designs combining IL-6 pathway modulators with strategies to manage G-CSF-mediated compensation.
Both bacterial and viral infections can trigger an overwhelming host response, leading to immunopathology and organ dysfunction. Multiple studies have reported dysregulated myeloid cell states in patients with bacterial sepsis or severe SARS-CoV-2 infection. However, their relevance to viral infections other than COVID-19, the factors driving their induction, and their role in tissue injury remain poorly understood. Here, we performed a multi-cohort analysis of single cell and bulk transcriptomic data from 1845 patients across 25 studies. Our meta-analysis revealed a conserved severity-associated gene signature pointing to emergency myelopoiesis (EM) and increased IL1R2 expression in monocytes and neutrophils from patients with bacterial sepsis, COVID-19, and influenza. Analysis of tocilizumab-treated COVID-19 patients showed that IL-6 signaling blockade partially reduces this signature and results in a compensatory increase in G-CSF. To validate the role of these cytokines in vivo, we used a mouse model of influenza infection that recapitulates severity-associated increases in IL1R2+ monocytes and IL1R2