Daily Sepsis Research Analysis
Three impactful studies span mechanism and practice: a Cell Reports paper identifies circulating FABP5 as a DAMP that amplifies septic inflammation and is targetable in mice; a multicenter cohort defines optimal local susceptibility thresholds (80–89% overall; ≥90% when critically ill) for empiric antibiotics in community-onset bacteremia; and macrophage ADAM8 is shown to worsen sepsis-induced cardiomyopathy by impairing efferocytosis, revealing a therapeutic target.
Summary
Three impactful studies span mechanism and practice: a Cell Reports paper identifies circulating FABP5 as a DAMP that amplifies septic inflammation and is targetable in mice; a multicenter cohort defines optimal local susceptibility thresholds (80–89% overall; ≥90% when critically ill) for empiric antibiotics in community-onset bacteremia; and macrophage ADAM8 is shown to worsen sepsis-induced cardiomyopathy by impairing efferocytosis, revealing a therapeutic target.
Research Themes
- DAMP-driven innate immune amplification in sepsis
- Data-informed empiric antibiotic stewardship thresholds
- Macrophage efferocytosis and sepsis-induced cardiomyopathy
Selected Articles
1. Circulating FABP5 released by dying macrophages function as a DAMP to exacerbate septic inflammation.
The study identifies oxidized circulating FABP5 as a DAMP released primarily from pyroptotic macrophages during late sepsis; it binds the intracellular domain of TLR4, triggering NF-κB/MAPK signaling and secondary inflammation. Neutralizing circulating FABP5 or preventing its release improved survival in septic mice, while cytosolic reduced FABP5 suppressed pyroptosis.
Impact: It reveals a previously unrecognized DAMP and a concrete, targetable pathway linking macrophage death to systemic inflammation and outcomes in sepsis.
Clinical Implications: Circulating FABP5 could serve as a biomarker for risk stratification and a therapeutic target (e.g., neutralizing antibodies) to dampen maladaptive inflammation in sepsis.
Key Findings
- Circulating FABP5 is elevated in sepsis patients and associates with adverse outcomes.
- Macrophage pyroptosis is the main source of circulating FABP5 in late sepsis.
- Extracellular oxidized FABP5 penetrates macrophages and binds the intracellular domain of TLR4, activating NF-κB and MAPK pathways.
- Cytosolic reduced FABP5 suppresses macrophage pyroptosis.
- Neutralizing or preventing release of circulating FABP5 improves survival in septic mice.
Methodological Strengths
- Translational approach integrating human clinical association with in vivo mechanistic mouse models.
- Mechanistic dissection of TLR4 intracellular binding and downstream NF-κB/MAPK signaling.
- Therapeutic intervention with blocking antibody demonstrating survival benefit.
Limitations
- Human cohort size and detailed confounder control are not provided in the abstract.
- Therapeutic efficacy is demonstrated in mice; human safety/efficacy remain untested.
- Temporal dynamics suggest late-sepsis specificity, which may limit early intervention utility.
Future Directions: Validate circulating FABP5 as a prognostic biomarker in multi-center cohorts and evaluate neutralizing strategies (antibodies or small molecules) in preclinical GLP studies progressing to early-phase trials.
2. Optimal Antimicrobial Susceptibilities for Empirical Administration in Adults with Community-Onset Bacteremia in the Emergency Department.
In 5,080 adults with community-onset monomicrobial bacteremia, empirical antibiotics aligned with a local susceptibility of 80–89% were associated with the lowest 30-day mortality. Critically ill patients benefited from regimens achieving ≥90% susceptibility, supporting tailored empiric thresholds by illness severity.
Impact: Provides empirically derived susceptibility thresholds to inform real-time empiric antibiotic selection, bridging antibiograms with patient outcomes.
Clinical Implications: Set local empiric prescribing targets to 80–89% susceptibility for most bacteremia and ≥90% for critically ill patients; incorporate into ED sepsis pathways and stewardship protocols.
Key Findings
- Across 5,080 patients, the 30-day mortality risk was lowest when empirical therapy aligned with 80–89% local susceptibility.
- In critically ill patients, ≥90% susceptibility regimens were associated with the best survival; 80–89% carried higher risk.
- Very low susceptibility strata (<60%, 60–69%, 70–79%) were each associated with progressively higher mortality (adjusted HRs 2.47, 1.68, 1.55).
Methodological Strengths
- Multicenter cohort with large sample size and pathogen-level prospective antibiogram construction.
- Mortality modeling with multivariable Cox regression adjusting for independent predictors.
Limitations
- Observational design with potential residual confounding and regional practice effects.
- Antibiotic choices and dosing heterogeneity; susceptibility categories may mask organism-specific nuances.
Future Directions: Prospective validation across diverse regions and integration into decision-support for ED sepsis care; evaluate impact on resistance and patient-centered outcomes.
3. ADAM8 in macrophages exacerbates sepsis-induced cardiomyopathy by impeding efferocytosis.
ADAM8 is upregulated in cardiac macrophages during sepsis; macrophage-specific deletion preserved cardiac function and improved survival in both LPS and CLP models. Mechanistically, ADAM8 impairs efferocytosis via MerTK shedding (sMer), and exogenous sMer reverses the protective phenotype, implicating the ADAM8–MerTK axis in SICM.
Impact: It links macrophage efferocytosis failure to septic cardiomyopathy and nominates ADAM8–MerTK as a druggable pathway.
Clinical Implications: Pharmacologic inhibition of ADAM8 or strategies to limit sMer generation may mitigate cardiac dysfunction in sepsis; ADAM8/sMer could serve as mechanistic biomarkers.
Key Findings
- ADAM8 expression is significantly upregulated in cardiac macrophages during sepsis (single-cell and immunofluorescence).
- Macrophage-specific ADAM8 knockout preserved cardiac function, reduced injury and apoptosis, and improved survival in LPS and CLP models.
- ADAM8 deficiency enhanced efferocytosis by increasing MerTK and reducing soluble Mer (sMer); exogenous sMer abrogated protection.
Methodological Strengths
- Two complementary sepsis models (LPS and CLP) with macrophage-specific genetic manipulation.
- Multi-omics/transcriptomic profiling linking phenotype to inflammatory signaling pathways.
Limitations
- Preclinical animal study without human validation of ADAM8/sMer in SICM patients.
- No pharmacologic inhibitor testing to complement genetic findings.
- Sample sizes and time course details are not stated in the abstract.
Future Directions: Quantify ADAM8 and sMer in SICM patients; develop/select ADAM8 inhibitors; test therapeutic modulation of the ADAM8–MerTK axis in large-animal models.