Daily ReportOct 18, 2026
Sepsis, October 18 edition
We read 17 papers and selected 3.
Summary
Today’s most impactful sepsis-related research spans mechanistic discovery and translational immunology. A secondary analysis of a randomized trial identified clarithromycin-associated inflammatory endotypes in community-acquired pneumonia, while two mechanistic studies identified MLKL and TRIM36 as potentially actionable regulators of sepsis-associated immune dysregulation and hyperinflammation.
Research Themes
- Inflammatory endotyping and immunomodulatory therapy
- Sepsis-associated immune paralysis and dendritic-cell dysfunction
- TLR4-driven hyperinflammation and therapeutic target discovery
Selected Articles
1. MLKL Orchestrates ER-Mitochondria Stress to Drive Dendritic Cell Pyroptosis and Immunoparalysis in Sepsis.
Using cecal ligation and puncture, lipopolysaccharide stimulation, and MLKL-deficient models, the study showed that MLKL promotes dendritic-cell pyroptosis and immune dysfunction during sepsis. MLKL deficiency reduced NLRP3–gasdermin D signaling, ER and mitochondrial stress, and reactive oxygen species, while restoring ER-phagy, dendritic-cell maturation, and CD4-positive T-cell responses.
Impact: This study connects MLKL, traditionally associated with necroptotic signaling, to organelle stress, dendritic-cell pyroptosis, and sepsis-associated immunoparalysis. The proposed MLKL–MFN2–ER-phagy axis offers a mechanistically coherent therapeutic target for restoring host immune competence.
Clinical Implications: The findings are preclinical and do not support immediate MLKL-directed therapy in patients. They provide a rationale for developing selective MLKL or downstream pathway inhibitors and for testing whether such interventions can restore antigen presentation without worsening infection control.
Key Findings
- Sepsis and lipopolysaccharide stimulation induced time-dependent MLKL activation and necroptosis-related signaling.
- MLKL deficiency attenuated NLRP3–gasdermin D-mediated pyroptosis, ER and mitochondrial stress, and reactive oxygen species production.
- Loss of MLKL preserved dendritic-cell maturation and costimulatory molecules, improved CD4-positive T-cell responses, and supported the MLKL–MFN2–ER-phagy mechanism.
Methodological Strengths
- The study combined an in vivo polymicrobial sepsis model with lipopolysaccharide stimulation and cellular mechanistic experiments.
- Genetic MLKL deficiency was complemented by analyses of signaling, organelle stress, autophagy, pyroptosis, dendritic-cell phenotype, and adaptive immune responses.
Limitations
- The evidence is primarily preclinical, and the abstract does not establish efficacy or safety of pharmacological MLKL inhibition in humans.
- Cecal ligation and puncture and lipopolysaccharide models may not fully reproduce the biological heterogeneity and timing of human sepsis-associated immune paralysis.
Future Directions: Future work should validate the pathway in human septic immune cells, develop selective and clinically deliverable MLKL-pathway inhibitors, define the therapeutic window, and determine whether immune restoration improves outcomes without increasing pathogen persistence.
INTRODUCTION: Sepsis induces systemic inflammation and immune dysregulation, leading to immunoparalysis characterized by dendritic cells (DCs) depletion and dysfunction. Mixed lineage kinase domain-like pseudokinase (MLKL) is an oranelle stress regulator; however, its role in DCs-mediated immune regulation during sepsis remains poorly defined. OBJECTIVES: This study aimed to elucidate the role of MLKL in sepsis-associated DCs dysfunction and to determine the underlying molecular mechanisms linking MLKL to immune dysregulation and disease severity. METHODS: Cecal ligation and puncture (CLP) was used to establish sepsis in wild-type (WT) and MLKL-deficient (MLKL
2. Effect of clarithromycin on the circulating inflammatory proteome in community-acquired pneumonia: a secondary analysis of the ACCESS trial.
This secondary analysis of the ACCESS randomized trial profiled 70 inflammatory proteins in 394 paired serum samples from 197 patients. Clarithromycin selectively reduced IL-6 at day 4, and an inflammatory endotype characterized by higher IFN-γ and globally elevated inflammatory proteins showed lower 90-day mortality with clarithromycin treatment.
Impact: The study links a clinical treatment effect to molecularly defined inflammatory heterogeneity rather than treating community-acquired pneumonia as a biologically uniform disease. It provides a rational framework for future endotype-guided immunomodulatory trials, including patients at risk of sepsis-related organ dysfunction.
Clinical Implications: Routine inflammatory-protein profiling cannot yet be recommended for treatment selection, but the findings support prospective validation of immune endotyping to identify pneumonia patients who may benefit from adjunctive clarithromycin or other immunomodulatory strategies.
Key Findings
- Clarithromycin selectively downregulated IL-6 at day 4, whereas several other inflammatory mediators decreased over time in both treatment groups.
- Unsupervised clustering identified two inflammatory endotypes with similar SOFA scores but distinct inflammatory protein profiles.
- In the endotype with higher IFN-γ and broadly elevated inflammatory proteins, clarithromycin treatment was associated with lower 90-day mortality.
Methodological Strengths
- The analysis was embedded in a randomized, double-blind controlled trial with a prespecified clinical treatment comparison.
- Paired longitudinal proteomic measurements enabled assessment of treatment-associated changes over time and exploratory molecular endotyping.
Limitations
- The biomarker analysis included a subset of ACCESS trial participants and was not designed to prospectively validate treatment-by-endotype interactions.
- The endotype findings are exploratory and may be affected by multiple testing, sample size, and limited generalizability beyond the studied community-acquired pneumonia population.
Future Directions: Prospective multicenter trials should validate the identified inflammatory endotypes, predefine biomarker-guided treatment strategies, and determine whether endotype-directed clarithromycin improves organ dysfunction and mortality in severe pneumonia or sepsis.
BACKGROUND: The ACCESS randomized double-blind controlled trial in hospitalized adults with community-acquired pneumonia (CAP) showed that adding clarithromycin to standard-of-care therapy accelerated clinical recovery within the first 72 hours after the commencement of treatment and reduced progression to organ dysfunction. RESEARCH QUESTION: Does clarithromycin treatment modulate the circulating inflammatory protein profile in CAP, and can inflammatory endotypes identify patient subgroups with distinct clinical responses? STUDY DESIGN AND METHODS: Serum samples obtained from ACCESS trial patients at baseline and 72 hours were profiled using the Olink Target 96 Inflammation panel. Patients were grouped by treatment arm and by achievement of the trial's composite primary endpoint. After quality control, 70 proteins from 394 paired samples across 197 patients were analyzed
3. TRIM36 catalyzes K63-linked ubiquitination of TAK1 to drive septic inflammation.
The study identified TRIM36 as an amplifier of TLR4 signaling in sepsis. TRIM36 directly bound TAK1 and catalyzed K63-linked ubiquitination required for TAK1 and NF-κB activation; Trim36 deletion improved survival and reduced cytokine production in an LPS-induced mouse model, while higher TRIM36 expression was associated with nonsurvival in a public patient dataset.
Impact: The work identifies a previously underrecognized ubiquitin-regulatory node that links TLR4 activation to TAK1–NF-κB-mediated septic inflammation. It combines human observations with mouse and macrophage experiments, strengthening the rationale for TRIM36 as a candidate biomarker and therapeutic target.
Clinical Implications: TRIM36 expression or pathway activity could eventually support risk stratification or targeted anti-inflammatory therapy, but clinical translation requires validation in well-characterized patient cohorts and confirmation that pathway inhibition does not impair antimicrobial host defense.
Key Findings
- TRIM36 expression increased in macrophages after lipopolysaccharide stimulation and was associated with nonsurvival in a public sepsis transcriptomic dataset.
- TRIM36 directly interacted with TAK1 and catalyzed its K63-linked ubiquitination, promoting TAK1 and NF-κB pathway activation.
- Trim36 genetic ablation in mice improved hypothermia and survival and reduced inflammatory cytokine production, while TRIM36 knockdown suppressed inflammatory signaling in human macrophages.
Methodological Strengths
- The study triangulated evidence across septic patient transcriptomic data, an in vivo mouse model, murine macrophages, and human THP-1-derived macrophages.
- Molecular interaction and post-translational modification experiments provided a mechanistic link between TRIM36 and TAK1 activation.
Limitations
- The principal sepsis efficacy model used lipopolysaccharide-induced inflammation, which does not fully reproduce polymicrobial human sepsis.
- The association between TRIM36 and nonsurvival was derived from a public transcriptomic dataset and does not establish causality or clinical assay performance.
Future Directions: Further studies should test TRIM36 inhibition in polymicrobial sepsis models, determine cell-type and disease-stage specificity, validate protein-level biomarkers in prospective cohorts, and evaluate whether selective targeting preserves pathogen clearance while reducing harmful inflammation.
BACKGROUND: The Toll-like receptor 4 (TLR4) pathway is critical for initiating innate immunity; however, its dysregulation drives pathological inflammation in diseases such as sepsis. METHODS: In the present study, we utilized septic patients, lipopolysaccharide (LPS)-induced mouse models, and LPS-treated mouse macrophages as well as human THP-1-derived macrophages to investigate the potential functions and molecular mechanisms of TRIM36 in sepsis. RESULTS: Here, we identify tripartite motif protein 36 (TRIM36) as a key positive regulator that amplifies TLR4 signaling. TRIM36 expression was robustly upregulated in macrophages upon lipopolysaccharide (LPS) challenge. Mechanistically, TRIM36 directly bound to TGF-β-activated kinase 1 (TAK1) and catalyzed its K63-linked ubiquitination, a prerequisite for the activation of TAK1 and the downstream nuclear factor-κB (NF-κB) pathway. Functionally, genetic ablation of Trim36 in mice attenuated hypothermia, improved survival, and reduced cytokine production in an LPS-induced sepsis model. Consistently, in vitro knockdown of TRIM36 in human macrophages blunted LPS-induced signaling and the secretion of proinflammatory mediators. Furthermore, analysis of a public transcriptomic dataset revealed that elevated TRIM36 levels were associated with non-survival in patients with sepsis.