Restoring a Lost Enzyme in Immune Cells Calms Runaway Inflammation in Septic Mice
Sepsis suppresses DPEP2 in monocytes, which tips lipid metabolism toward inflammation. Delivering Dpep2 mRNA with nanoparticles improved outcomes in septic mice.
Résumé
Sepsis kills partly through runaway inflammation, and treatments that safely restrain it are lacking. Using single-cell and bulk RNA sequencing of patient blood, researchers found that the lipid-metabolizing enzyme DPEP2 is sharply reduced in circulating monocytes during early sepsis. Lower DPEP2 tracked with higher inflammation and illness severity scores. In mice and cell models, losing DPEP2 in macrophages worsened inflammation, organ damage, and survival. The mechanism: sepsis induces the transcription factor EGR1, which represses DPEP2. That blocks breakdown of leukotriene D4, pushing metabolism toward excess prostaglandin E2 and stronger NF-κB signaling. Lipid nanoparticles delivering Dpep2 mRNA to monocytes/macrophages reduced inflammation and organ injury in septic mice. This is preclinical work, but it points to DPEP2 as both a biomarker and a therapeutic target.
Résumé détaillé
Sepsis, a life-threatening organ dysfunction caused by a dysregulated response to infection, accounts for roughly 20% of global deaths. Antibiotics and organ support remain the mainstays of care. Excessive early inflammation driven by monocytes and macrophages contributes substantially to mortality, yet reliable immunotherapy targets are scarce. This study asked whether a metabolic gene in these cells could be a handle for controlling that response.
The team reanalyzed single-cell RNA sequencing of blood mononuclear cells from five early-sepsis patients and five healthy controls (80,063 cells after quality control). They then added bulk RNA-seq from five further patients and five controls. Monocytes showed the largest gene-expression reprogramming in sepsis and split into four subclusters. The largest, Mono1, was the only one that shrank in sepsis, and it was enriched for immune and metabolic programs. Intersecting Mono1 markers with bulk differentially expressed genes yielded ten overlapping genes. The team chose DPEP2, a lipid-metabolism enzyme enriched in monocytes/macrophages that was consistently lower in all septic patients. They confirmed the drop by quantitative PCR.
In a further cohort of 36 early-sepsis patients and 36 uninfected volunteers, flow cytometry showed lower DPEP2 in CD11b+CD14+ monocytes but not in T cells. In septic patients, the proportion of DPEP2-positive monocytes correlated negatively with SOFA (r = -0.68) and APACHE-II (r = -0.65) scores. The abstract also reports links to inflammation, disease progression, and outcomes.
Per the abstract, Dpep2 knockdown amplified macrophage inflammatory responses in vitro. Macrophage-specific Dpep2 loss in septic mice reduced survival and worsened inflammation and organ damage. Sepsis induces the transcription factor EGR1, which represses Dpep2. Without DPEP2, leukotriene D4 (LTD4) is not enzymatically cleaved. The accumulating LTD4 redirects metabolic flux toward prostaglandin E2 (PGE2) overproduction, which amplifies NF-κB activation and LPS-induced cytokine release. Lipid nanoparticles carrying Dpep2 mRNA, targeted to monocytes/macrophages, reduced inflammation and organ damage in septic mice.
The work nominates DPEP2 as a prognostic biomarker and an mRNA-based therapeutic target. It also links a specific EGR1–DPEP2–LTD4–PGE2 axis to sepsis hyperinflammation. Caveats: the human sequencing cohorts are small, the human cohort is observational, and the therapeutic evidence comes from mouse models. Only part of the full text was available for this summary, so detailed in vivo quantitative results are not reproduced here. Safety, dosing, timing relative to the later immunosuppressive phase of sepsis, and human efficacy remain untested.
Principales conclusions
- DPEP2 was consistently downregulated in peripheral monocytes of early-sepsis patients across single-cell, bulk RNA-seq, and PCR data.
- In 36 septic patients, DPEP2-positive monocyte proportion correlated negatively with SOFA (r = -0.68) and APACHE-II (r = -0.65) scores.
- Macrophage-specific Dpep2 loss worsened inflammation, organ damage, and survival in septic mice.
- Sepsis-induced EGR1 represses Dpep2, raising LTD4 and shifting metabolism toward PGE2 overproduction and amplified NF-κB signaling.
- Lipid nanoparticle delivery of Dpep2 mRNA to monocytes/macrophages reduced inflammation and organ damage in septic mice.
Méthodologie
The study integrated scRNA-seq (5 sepsis patients vs 5 controls) with bulk RNA-seq (5 vs 5) to prioritize DPEP2. It then used a flow cytometry cohort (36 sepsis vs 36 controls) for clinical correlation. Mechanism and therapy were tested in macrophage knockdown models and septic mice, including macrophage-specific Dpep2 deletion and LNP-delivered Dpep2 mRNA.
Limites de l'étude
The patient sequencing cohorts are small and the clinical correlations are observational, so causation in humans is unproven. Therapeutic benefit was shown only in mouse sepsis models, which imperfectly reflect human disease. The full text was truncated, so detailed in vivo effect sizes and safety data could not be assessed.
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