Daily Sepsis Research Analysis
Analyzed 47 papers and selected 3 impactful papers.
Summary
Three mechanistic studies redefine sepsis biology and potential interventions: (1) FGF13 drives ERK/HIF-1α–dependent aerobic glycolysis in endothelial cells and macrophages, worsening septic lung injury; (2) a ketogenic diet reshapes the gut microbiota to generate azelaic acid that resolves lung inflammation during sepsis; (3) lactate directly lactylates NLRP3 to accelerate inflammasome assembly and pyroptosis, linking immunometabolism to inflammation.
Research Themes
- Immunometabolism and inflammasome regulation in sepsis
- Diet–microbiome–metabolite axis as a therapeutic lever
- Endothelial and myeloid signaling driving septic lung injury
Selected Articles
1. FGF 13 functions as a regulator of the ERK/aerobic glycolysis axis in the inflammatory state during septic lung injury.
Using conditional genetics and pharmacology, the authors show that FGF13 scaffolds TAK1/MEK/ERK signaling to amplify HIF‑1α–driven aerobic glycolysis in endothelial cells and macrophages, thereby worsening septic lung injury. ERK inhibition abrogated FGF13-induced inflammation, and HIF‑1α overexpression reversed protection from Fgf13 deletion.
Impact: Identifies FGF13 as a nodal regulator linking ERK signaling to immunometabolic reprogramming in septic lung injury, revealing druggable axes (ERK/HIF‑1α/glycolysis).
Clinical Implications: Suggests therapeutic potential for ERK pathway inhibitors or targeting FGF13-driven glycolysis to mitigate septic lung injury; FGF13 expression could inform risk stratification.
Key Findings
- FGF13 is downregulated in lung endothelial cells and macrophages of septic patients and mice.
- Conditional Fgf13 deletion protects against, and overexpression worsens, septic lung inflammation.
- FGF13 scaffolds TAK1/MEK/ERK to enhance HIF‑1α–regulated aerobic glycolysis under inflammatory conditions.
- ERK inhibitor SCH772984 abolishes FGF13-driven inflammatory exacerbation; HIF‑1α overexpression negates protection from Fgf13 knockout.
Methodological Strengths
- Use of conditional knockout and overexpression mouse models to establish causality.
- Mechanistic dissection of TAK1/MEK/ERK–HIF‑1α axis with pharmacologic inhibition and genetic rescue.
Limitations
- Preclinical models (murine sepsis) may not fully recapitulate human pathophysiology.
- Translational feasibility of targeting FGF13 or ERK/HIF‑1α in acute sepsis remains to be established.
Future Directions: Validate FGF13 as a biomarker and therapeutic target in human sepsis cohorts; test ERK/HIF‑1α/glycolysis modulators in clinically relevant models and early-phase trials.
Fibroblast growth factor 13 (FGF13) belongs to the FGF homologous factor subfamily, members of which lack signal peptides. In this study, we demonstrate that FGF13 is significantly downregulated in endothelial cells and macrophages in the lungs of septic patients and septic mice. However, the role of FGF13 in sepsis and the underlying mechanism are largely unknown. By using mice with conditional Fgf13 knockout and FGF13 overexpression, we find that FGF13 accelerates septic lung injury by promoting inflammatory activation of endothelial cells and macrophages. Specifically, FGF13 functions as a scaffold protein in TAK1/MEK/ERK signaling to promote hypoxia-inducible factor (HIF)-1α-regulated aerobic glycolysis in the inflammatory state. Meanwhile, the protective effect of conditional Fgf13 knockout is abolished in HIF-1α-overexpressing mice. In addition, SCH772984 (a selective antagonist of ERK signaling) abolishes the aggravation of inflammation in lungs induced by FGF13 overexpression. Our findings demonstrate that FGF13 promotes inflammatory activation upon septic lung injury through the ERK/aerobic glycolysis axis, thereby accelerating the progression of septic lung injury.
2. Ketogenic diet alleviates septic lung injury via microbial gut-lung axis.
A ketogenic diet reprograms the gut microbiota to enrich strains expressing an FMO that converts dietary oleic acid into azelaic acid, which traffics to the lung during sepsis to promote neutrophil apoptosis and expansion of MerTK+ macrophages, thereby resolving inflammation and mitigating lung injury.
Impact: Uncovers a diet–microbe–metabolite–immune circuit with translational potential, suggesting dietary or microbial/metabolite therapies to modulate sepsis lung pathology.
Clinical Implications: Motivates evaluation of ketogenic-like nutritional strategies, FMO-bearing probiotics, or azelaic acid administration as adjuncts in sepsis, with careful safety and metabolic monitoring.
Key Findings
- Ketogenic diet alleviates sepsis-induced lung injury via a gut–lung microbial axis.
- KD enriches Limosilactobacillus reuteri and Lactiplantibacillus plantarum in mice and humans.
- Specific strains express FMO that converts oleic acid into azelaic acid, which traffics to lung during sepsis.
- Azelaic acid promotes neutrophil apoptosis and expands MerTK+ macrophages to resolve inflammation.
Methodological Strengths
- Cross-species evidence integrating mouse models with human microbiome observations.
- Mechanistic identification of bacterial FMO and metabolite (azelaic acid) mediating lung immune effects.
Limitations
- Human data appear observational; causal mechanisms are primarily demonstrated in mice.
- Safety and feasibility of ketogenic diets or metabolite supplementation in acute sepsis remain uncertain.
Future Directions: Test FMO-expressing probiotic strains or azelaic acid as therapeutics; define dietary parameters and patient subgroups for safe translation in sepsis.
Sepsis is characterized by impaired immunity to infection, leading to multi-organ dysfunction, with the lung being the most vulnerable organ. Here, we show that ketogenic diet (KD) alleviates sepsis-induced lung injury through a microbial-gut-lung axis. KD alters the gut microbiota in mice and humans, enriching Limosilactobacillus reuteri and Lactiplantibacillus plantarum. Specific strains of these species produce a flavin-dependent monooxygenase (FMO) that converts oleic acid in KD into azelaic acid (AZA). During sepsis, AZA translocates to the lung, where it promotes neutrophil apoptosis and expands MerTK
3. Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation.
Lactate generated by aerobic glycolysis directly modifies NLRP3 via AARS2-mediated lactylation at K24 and K565, enhancing ASC recruitment and inflammasome assembly to drive pyroptosis. Inhibiting lactate production reduced inflammatory responses in a polymicrobial sepsis model.
Impact: Defines a direct post-translational modification (lactylation) of NLRP3 as a metabolic checkpoint for inflammasome activation, opening avenues to target immunometabolism in sepsis.
Clinical Implications: Supports exploration of glycolysis/LDH inhibitors or modulators of protein lactylation/AARS2 as strategies to temper excessive inflammasome activity in sepsis.
Key Findings
- Endogenous lactate promotes NLRP3 inflammasome assembly by facilitating ASC recruitment.
- NLRP3 is lactylated by AARS2 at K24 and K565, enhancing inflammasome activation.
- In vivo inhibition of lactate production alleviates inflammation in polymicrobial sepsis.
Methodological Strengths
- LC-MS/MS mapping of lactylation sites with functional mutational validation.
- Integration of cellular mechanistic assays with in vivo sepsis model readouts.
Limitations
- Specificity and druggability of AARS2-mediated lactylation remain to be established in vivo.
- Systemic inhibition of glycolysis may carry safety risks in critically ill patients.
Future Directions: Develop selective modulators of protein lactylation or NLRP3–AARS2 interaction; define therapeutic windows for metabolic interventions in sepsis.
Bacteria-infected macrophages undergo pyroptosis to release inflammatory cytokines, which contributes to host defense. It has been known that activated macrophages involve metabolic reprogramming. However, the metabolic changes and the role of metabolites in pyroptotic macrophages are not fully understood. Here, we revealed that aerobic glycolysis product, lactate, could promote NLRP3 inflammasome activation induced pyroptosis. We found that endogenous lactate facilitates ASC recruitment to NLRP3 cores on the organelle membrane, thus inducing NLRP3 inflammasome complex formation. Mechanistically, we identified NLRP3 as a target protein modified by lactate, which is lactylated by AARS2. We confirmed lactylated sites on NLRP3 by LC-MS/MS analysis and verified that lactylation at K24 and K565 of NLRP3 facilitates inflammasome activation in macrophage. In vivo, inhibition of lactate production alleviates inflammatory responses in polymicrobial sepsis. Overall, our results indicate the role of lactate in regulating macrophage pyroptosis and the crosstalk between metabolism and innate immunity.