Daily Sepsis Research Analysis
Analyzed 16 papers and selected 3 impactful papers.
Summary
Top studies today integrate bone–immune crosstalk with sepsis vulnerability, identify peripheral bioenergetic signatures linked to mortality in early sepsis, and uncover a macrophage mitochondrial control node amenable to pharmacologic modulation. Mechanistic advances (USP26/IL4I1–tryptophan axis; DRP1 SUMOylation) align with translational signals (engineered exosomes, phytosterol intervention) and a prospective human cohort linking PBMC respiration to 3‑month outcomes.
Research Themes
- Immunometabolism and bone–immune crosstalk in sepsis
- Mitochondrial quality control and prognostic bioenergetics
- Macrophage polarization and lung injury modulation
Selected Articles
1. Osteoblastic USP26 regulates B lymphopoiesis by endogenous tryptophan metabolites.
Downregulation of osteoblastic USP26 impairs IL4I1-dependent tryptophan metabolism, reduces indole-3-acetic acid, compromises B lymphopoiesis, and increases sepsis mortality in mice. Bone-targeted exosomal restoration of USP26 rescues bone formation, B-cell output, and infection resistance, establishing a bone–immune metabolic axis as a modifiable determinant of sepsis vulnerability.
Impact: Reveals a previously unappreciated osteoblast-driven metabolic control of humoral immunity that directly modifies sepsis outcomes, and demonstrates a feasible delivery strategy using bone-targeted exosomes.
Clinical Implications: In aging or osteoporotic patients at high infection risk, targeting the USP26/IL4I1–AHR axis may augment B-cell competence and reduce sepsis susceptibility; bone-targeted biologics could complement vaccination and antimicrobial stewardship.
Key Findings
- Osteoblastic USP26 is downregulated in senescent bone and impairs osteoblast differentiation while promoting IL4I1 degradation.
- Collapse of the tryptophan metabolic axis reduces indole-3-acetic acid and compromises B lymphopoiesis.
- Osteoblast-specific Usp26 knockout mice exhibit decreased B cells and earlier death under sepsis conditions.
- Bone-targeted exosomal USP26 restores bone formation, rescues B-cell output, and improves infection resistance.
Methodological Strengths
- Integrative approach combining patient and mouse data with transcriptomics, targeted metabolomics, and in vivo/in vitro validation.
- Genetic causality via osteoblast-specific conditional knockout and therapeutic rescue with engineered, bone-targeting exosomes.
Limitations
- Preclinical study without human interventional validation or clinical endpoints.
- Detailed sepsis model parameters and sample sizes for each experiment are not specified in the abstract.
Future Directions: Translate USP26/IL4I1–AHR axis modulation to early-phase clinical studies in osteoporotic or immunosenescent populations; refine bone-targeted exosome delivery and assess vaccine responsiveness and bloodstream infection rates.
INTRODUCTION: Bone loss is associated with declines in immune function. Osteoblasts, as key regulators of bone formation and the bone marrow niche, may orchestrate this coupled deterioration, but the underlying molecular mechanisms require further elucidation. OBJECTIVES: This study aims to explore the molecular mechanisms by which functional degeneration of osteoblasts leads to immune decline in osteoporosis. METHODS: Immune cell populations in peripheral blood were analyzed in both osteoporotic patients and mice. USP26 expression was assessed in senescent osteoblasts and bones. Bone formation, B lymphopoiesis, and susceptibility to sepsis were evaluated in mice with osteoblast-specific conditional knockout of Usp26. A combination of transcriptomics, targeted metabolomics, and in vivo/in vitro experiments involving tryptophan metabolite supplementation and inhibition were performed to identify associated niche metabolic factors. Finally, the therapeutic potential of USP26 restoration was evaluated by administering USP26-modified, bone-targeting exosomes in osteoporotic and septic mouse models. RESULTS: In this study, we have identified the downregulation of USP26 in osteoblasts as a critical mechanism bridging bone loss and immune dysfunction. Mechanistically, the reduced USP26 levels impede osteoblast differentiation while facilitating the ubiquitin-mediated degradation of interleukin-4-induced protein 1 (IL4I1). This impairment collapses the tryptophan metabolic axis, specifically reducing the production of the endogenous tryptophan-derived indole metabolite, indole-3-acetic acid (IAA) and compromising B lymphopoiesis. Consistent with this, we observe the mice with USP26 deficiency in osteoblasts died earlier in sepsis conditions with decreased B cells. The bone-targeted delivery of USP26 in osteoporotic mice via engineered exosomes restored bone formation, rescued B cell production and improved infection resistance. CONCLUSION: Our findings establish osteoblastic USP26 as a dual regulator of bone formation and immune activation, indicating that modulating osteoblast function and targeting the USP26/IL4I1-AHR signaling axis may represent a promising therapeutic strategy for treating immune deficiency associated with age-related bone loss in clinical settings.
2. β - sitosterol promotes the SUMOylation of DRP1 in alveolar macrophages and alleviates sepsis-associated acute lung injury.
β‑sitosterol reduces ROS and M1 polarization of alveolar macrophages and preserves mitochondrial integrity by promoting SUMO2/3‑mediated SUMOylation and lysosomal degradation of DRP1. These effects mitigate sepsis‑associated acute lung injury in mice, nominating DRP1 SUMOylation as a druggable node in macrophage immunometabolism.
Impact: Identifies a specific posttranslational modification of DRP1 as a lever to control macrophage polarization and mitochondrial quality, with a readily available phytosterol demonstrating in vivo efficacy.
Clinical Implications: While preclinical, targeting DRP1 SUMOylation could complement supportive care in sepsis‑related lung injury. β‑sitosterol or derivatives may inform adjunctive therapies pending pharmacokinetic, safety, and dosing studies.
Key Findings
- β‑sitosterol suppressed ROS generation and M1 polarization in LPS‑stimulated MH‑S alveolar macrophages.
- Mechanistically, β‑sitosterol promoted SUMO2/3‑mediated SUMOylation of DRP1, driving its lysosomal degradation and preserving mitochondrial function.
- DRP1 overexpression abrogated β‑sitosterol’s mitochondrial protection and anti‑inflammatory effects.
- Oral β‑sitosterol alleviated sepsis‑associated acute lung injury in CLP mice.
Methodological Strengths
- Complementary in vivo CLP mouse model and in vitro macrophage assays with convergent mechanistic readouts.
- Causality supported by genetic perturbation (DRP1 overexpression) reversing the pharmacologic phenotype.
Limitations
- Preclinical data without human pharmacokinetic/safety evaluation or clinical endpoints.
- Survival benefit and optimal dosing window are not detailed in the abstract.
Future Directions: Define pharmacokinetics, target engagement, and safety of β‑sitosterol; test DRP1 SUMOylation modulators in large‑animal sepsis models; assess synergy with lung‑protective ventilation and antibiotics.
Acute lung injury (ALI) represents the most frequent complication of sepsis; however, effective drug-based interventions are still unavailable. β-sitosterol (BS) has demonstrated anti-inflammatory effects and protective properties on alveolar epithelial barriers. This study investigated the mechanism by which BS targets alveolar macrophages to attenuate sepsis-associated acute lung injury (SALI) via in vivo and in vitro experiments. Sepsis was induced in mice through cecal ligation and puncture (CLP), and BS was administered orally. An in vitro model of lipopolysaccharide (LPS)-induced MH-S cell infection validated the proposed mechanism. Macrophage polarization and mitochondrial function were assessed using flow cytometry, electron microscopy, and Western blot analysis. Results showed that BS suppressed reactive oxygen species (ROS) production and M1 macrophage polarization in LPS-stimulated MH-S cells. Mechanistically, BS promoted lysosomal degradation of dynamin-related protein 1 (DRP1) via SUMO2/3-mediated SUMOylation, preserving mitochondrial integrity and function. Transfection of MH-S cells with DRP1 plasmid abolished the BS-mediated mitochondrial protection mechanism, reducing inhibition of oxidative stress and M1 polarization. In summary, BS inhibits M1 polarization of alveolar macrophages by promoting DRP1 SUMOylation, effectively alleviating SALI in mice. These findings support BS as a potential therapeutic agent for SALI, providing a theoretical basis for clinical application.
3. Progression of peripheral blood mononuclear cell mitochondrial function during the early phase of sepsis in intensive care unit patients.
In a prospective ICU cohort, PBMC bioenergetics were elevated across the first week of sepsis, with higher basal respiration associating with increased 3‑month mortality. Upregulation of SDHB and ATP5F1A paralleled functional changes, suggesting adaptive or maladaptive immune cell mitochondrial remodeling with prognostic significance.
Impact: Provides time-resolved, human in vivo evidence that immune cell bioenergetics track with outcomes in early sepsis, challenging simple ‘bioenergetic failure’ narratives and informing biomarker and therapeutic target development.
Clinical Implications: Serial PBMC respirometry could support risk stratification and guide trials of immunometabolic modulators in sepsis; targets within oxidative phosphorylation may be prioritized for intervention.
Key Findings
- PBMC basal, ATP-linked, maximal, and proton leak respiration were increased in sepsis patients versus matched controls at all measured time points in the first ICU week.
- Expression of SDHB (complex II) and ATP5F1A (complex V) was increased in sepsis patients.
- Higher basal respiration associated with increased 3‑month mortality (HR 3.794; 95% CI 1.018–14.149; p=0.047).
Methodological Strengths
- Prospective design with age- and sex-matched controls and repeated measures across the first ICU week.
- Combined functional respirometry with gene expression analysis to align bioenergetics and molecular signatures.
Limitations
- Single-centre study with a small sample size, limiting generalizability and precision (wide CI for mortality association).
- Potential confounding from treatments and comorbidities; PBMCs may not fully reflect organ-specific pathophysiology.
Future Directions: Validate PBMC bioenergetic biomarkers in larger, multicentre cohorts; integrate with metabolomics and cytokine profiling; test whether immunometabolic modulators normalize maladaptive respiration and improve outcomes.
Sepsis is associated with high rates of multiorgan failure and mortality. Altered mitochondrial function is an essential component of the early sepsis syndrome. However, its progression over time in peripheral blood mononuclear cells (PBMCs) is thus far unclear. Our purpose was to investigate this in the early phase of sepsis in ICU patients. A single-centre prospective observational cohort study was conducted in sepsis patients and compared with age- and sex-matched controls. Mitochondrial function was measured in PBMCs thrice during the first ICU week. RT-qPCR was used for semi-quantitative analysis of expression of genes involved in oxidative phosphorylation. Secondary endpoints included associations between mitochondrial function and (I) sepsis severity and (II) clinical outcomes, including 3-month mortality. Basal, ATP-linked, maximal and proton leak associated respiration were increased in sepsis patients (n = 25) compared to matched controls (n = 24) at all time points. This was associated with increased expression of SDBH (complex II) and ATP5F1A (complex V). Increased basal respiration was associated with 3-month mortality (HR 3.794, 95% CI 1.018-14.149, p = 0.047). No differences were observed in other secondary outcomes. PBMC mitochondria were shown to have an increased respiratory rate during the first week of sepsis. Moreover, a progressive increase was negatively associated with 3-month survival.