Daily Sepsis Research Analysis
Analyzed 41 papers and selected 3 impactful papers.
Summary
Analyzed 41 papers and selected 3 impactful articles.
Selected Articles
1. EGFR orchestrates neutrophil activation and NETosis via CEBPβ-dependent PGLYRP1 induction.
This mechanistic study identifies EGFR as a neutrophil-intrinsic master regulator of pathological NETosis in sepsis via a MAPK14–CEBPβ–PGLYRP1–TREM‑1 circuit. Genetic ablation of EGFR in neutrophils reduced NETs, cytokine storm, tissue injury, and improved survival in polymicrobial sepsis; rescue experiments validated pathway centrality.
Impact: It uncovers a previously unrecognized, targetable EGFR-centered axis linking receptor signaling to NETosis, offering translational avenues to dampen neutrophil-driven immunopathology in sepsis.
Clinical Implications: Therapeutic targeting of EGFR or downstream nodes (PGLYRP1, TREM‑1) could attenuate NETosis and systemic inflammation in sepsis. Findings support exploration of repurposing EGFR inhibitors or TREM‑1 antagonists with careful safety evaluation.
Key Findings
- EGFR expression is elevated in sepsis patient neutrophils and correlates with disease severity.
- Neutrophil-specific EGFR deletion improves survival and reduces NETs, cytokines, and tissue injury in polymicrobial sepsis.
- EGFR recruits MAPK14 to phosphorylate CEBPβ, driving PGLYRP1 transcription and NETosis via autocrine TREM‑1 signaling.
- Recombinant PGLYRP1 or CEBPβ overexpression reverses the protection in EGFR-deficient neutrophils, confirming pathway centrality.
Methodological Strengths
- Integrated human patient neutrophil data with in vivo genetic loss-of-function models and survival outcomes.
- Mechanistic dissection using co-immunoprecipitation, signaling pathway interrogation, and gain/loss-of-function rescue experiments.
Limitations
- Preclinical study without interventional human trials; translational efficacy and safety remain untested.
- Potential class-specific toxicities of EGFR inhibition in sepsis contexts were not evaluated.
Future Directions: Evaluate pharmacologic modulation of the EGFR–PGLYRP1–TREM‑1 axis in large-animal sepsis models and early-phase human studies; assess combination strategies with antimicrobial and organ support therapies.
Excessive neutrophil activation and neutrophil extracellular trap (NET) release drive systemic inflammation and organ injury in sepsis, yet the upstream regulatory pathways remain incompletely defined. Here, we identify epidermal growth factor receptor (EGFR) as a critical neutrophil-intrinsic regulator of NETosis. EGFR expression was markedly elevated in neutrophils from patients with sepsis and correlated with disease severity. Neutrophil-specific EGFR deletion in mice improved survival after polymicrobial sepsis by reducing cytokine storm, tissue injury, and NET formation. Mechanistically, EGFR associated with CCAAT/enhancer-binding protein beta (CEBPβ) and recruited Mitogen-activated protein kinase 14 (MAPK14) to phosphorylate CEBPβ, promoting its nuclear localization and transcriptional activation of peptidoglycan recognition protein 1 (PGLYRP1). Elevated PGLYRP1, in turn, amplified NETs release via autocrine engagement of triggering receptor expressed on myeloid cell-1 (TREM-1), establishing a feed-forward inflammatory loop. Administration of recombinant PGLYRP1 or forced CEBPβ overexpression reversed the protection conferred by EGFR deficiency, confirming the centrality of this axis. These findings define an unrecognized EGFR-MAPK14-CEBPβ-PGLYRP1-TREM1 circuit that links receptor signaling to pathological NETosis and highlight a promising therapeutic target to attenuate neutrophil-driven immunopathology in sepsis.
2. Molecular Landscape and Predictive Significance of Programmed Cell Death-Related Genes in Sepsis.
Using GEO transcriptomes, the authors delineated PCD-related gene networks in sepsis, identified 262 hub genes and seven prognostic PRGs, and built a high-performing diagnostic model across eight machine-learning algorithms, validated with scRNA-seq. Neutrophil-associated genes (e.g., S100A9, KLHL3) emerged as potential targets.
Impact: Provides a PCD-focused systems framework and validated diagnostic model for sepsis, highlighting neutrophil-linked targets and enabling stratified biomarker development.
Clinical Implications: If prospectively validated, the model and PRGs could improve early sepsis diagnosis and risk stratification, guiding timely interventions and enabling mechanism-guided trials.
Key Findings
- WGCNA identified 14 gene modules in sepsis, with the turquoise module most strongly associated; 262 hub genes were enriched in apoptotic pathways.
- Seven prognostic PCD-related feature genes were defined and used to construct a diagnostic model via eight machine-learning algorithms with high discrimination.
- scRNA-seq validation linked key genes (e.g., S100A9, KLHL3) to neutrophils, reinforcing biological plausibility and therapeutic relevance.
Methodological Strengths
- Multi-cohort transcriptomic integration with WGCNA and eight distinct machine-learning classifiers.
- Independent validation at single-cell resolution to confirm cell-type specificity of feature genes.
Limitations
- Retrospective analyses of public datasets; lacks prospective, external clinical validation and standardized sampling.
- Heterogeneity in platforms and cohorts may introduce confounding despite bioinformatic adjustments.
Future Directions: Prospective multi-center validation of the diagnostic model, integration with clinical variables, and functional interrogation of lead PRGs in experimental systems.
Sepsis, a systemic inflammatory response to infection, remains a significant health challenge with high morbidity and mortality rates. The molecular mechanisms underlying sepsis, particularly the role of programmed cell death (PCD), are not fully understood. This study is aimed at elucidating the transcriptomic changes associated with sepsis, emphasizing PCD, and identifying potential diagnostic biomarkers. Transcriptome data from sepsis and control samples were extracted from the GEO website. Differential expression analysis identified genes perturbed in sepsis. WGCNA revealed 14 highly connected modules, with the turquoise module showing the strongest association with sepsis. A set of 262 hub genes was identified, which were mainly associated with apoptotic signaling pathways. Seven prognostic-related overlapping feature genes (PRGs) were identified. More importantly, the diagnostic model, constructed using eight machine learning algorithms, exhibited high efficacy in distinguishing sepsis patients from controls. The validation of feature genes at the scRNA-seq level adds a layer of robustness to our conclusions. The strong association of genes like S100A9 and KLHL3 with neutrophils, pivotal players in sepsis, suggests potential avenues for therapeutic targeting. Our comprehensive analysis has unveiled the significant role of PCD in sepsis. The insights gained from this study provide a foundation for future therapeutic interventions.
3. Aldehyde Dehydrogenase-2 Alleviates Septic Myocardial Injury by Inhibiting Caspase-11-Mediated Noncanonical Pyroptosis.
ALDH2 activation (Alda‑1) mitigated septic cardiomyopathy in CLP mice, and ALDH2 overexpression protected cardiomyocytes from LPS injury. Mechanistically, ALDH2 suppressed caspase‑11 noncanonical pyroptosis and interacted with HMGB1, RAGE, and GSDMD, highlighting a targetable pathway in septic myocardial injury.
Impact: Links a druggable metabolic enzyme (ALDH2) to inhibition of noncanonical pyroptosis in septic myocardium, suggesting repurposing of Alda‑1 for sepsis-induced cardiomyopathy.
Clinical Implications: ALDH2 agonism could be explored as an adjunct therapy to prevent or treat sepsis-induced cardiomyopathy, pending safety and efficacy in large-animal models and humans.
Key Findings
- Alda‑1 significantly attenuated CLP-induced cardiac dysfunction and myocardial damage in vivo.
- ALDH2 overexpression reduced LPS-induced cardiomyocyte injury and decreased caspase‑11, HMGB1, and RAGE expression.
- Co-immunoprecipitation revealed ALDH2 interactions with HMGB1, RAGE, and GSDMD, implicating suppression of noncanonical pyroptosis.
Methodological Strengths
- Use of CLP sepsis model with functional (echocardiography) and ultrastructural (TEM) assessments.
- Complementary in vitro gain-of-function and protein–protein interaction analyses (co-IP).
Limitations
- Findings are preclinical with no human interventional data; H9C2 cell line may not fully recapitulate human cardiomyocytes.
- Dose–response, timing, and safety of Alda‑1 in sepsis were not comprehensively evaluated.
Future Directions: Test ALDH2 agonists in large-animal sepsis cardiomyopathy models, define optimal dosing/timing, and evaluate synergy with standard sepsis care.
PURPOSE: The purpose of this study is to investigate the role of aldehyde dehydrogenase-2 (ALDH2) in septic myocardial injury, focusing on noncanonical pyroptosis. METHODS: In vivo, C57BL/6J mice were divided into five groups: Sham, cecal ligation and puncture (CLP), CLP + Alda-1 (ALDH2 agonist), Sham + dimethyl sulfoxide (DMSO, solvent control), and CLP + DMSO. Cardiac function and histological/ultrastructural changes were assessed via echocardiography, hematoxylin-eosin (HE) staining, and transmission electron microscopy (TEM). Tumor necrosis factor- RESULTS: In vivo, Alda-1 significantly attenuated CLP-induced cardiac dysfunction and reduced myocardial histological damage and ultrastructural impairment. In vitro, ALDH2 overexpression lowered LPS-induced H9C2 cell viability, CK-MB, and LDH release. Upregulating ALDH2 significantly reduced caspase-11, HMGB1, and RAGE expression. CO-IP showed ALDH2 interacted with HMGB1, RAGE, and GSDMD. CONCLUSION: ALDH2 protects the myocardium from septic injury by inhibiting caspase-11-mediated noncanonical pyroptosis, possibly via direct interactions with GSDMD, HMGB1, and RAGE.