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Phosphorylated toll-like receptor 4 defines a high-risk sepsis endotype

Madita Mühlhaus1, Birte Dyck1, Andrea Witowski1,2

  • 1Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Ruhr-University Bochum, Knappschaft Kliniken Universitätsklinikum Bochum, Zentrum für perioperative Präzisionsmedizin, ZKF1, Universitätsstraße 150, Bochum, 44801, Germany.

Critical Care (London, England)
|May 30, 2026
PubMed
Abstract

Insights

Toll-like receptor 4 (TLR4) activation in sepsis is not universal but present in a high-risk subgroup. Elevated TLR4 activation strongly correlates with increased 30-day mortality in sepsis patients.

Area of Science:

  • Immunology
  • Critical Care Medicine
  • Molecular Biology

Background:

  • Sepsis involves a dysregulated immune response to infection.
  • Toll-like receptor 4 (TLR4) is crucial for pathogen recognition and inflammation.
  • Previous TLR4 inhibitor trials in sepsis failed clinically despite preclinical success.

Purpose of the Study:

  • Quantify in vivo TLR4 activation in sepsis patients.
  • Determine the association between TLR4 activation and 30-day survival.
  • Investigate TLR4 as a potential sepsis biomarker.

Main Methods:

  • Collected peripheral blood mononuclear cells from 100 sepsis patients.
  • Measured TLR4 activation via receptor phosphorylation using proximity ligation assay on days 1 and 4.
  • Analyzed survival using Kaplan-Meier curves and Cox regression.

Main Results:

  • Overall TLR4 activation was low, but a subset of patients exhibited increased activation.
  • Higher TLR4 activation was significantly associated with reduced 30-day survival.
  • Elevated activation increased mortality risk (Day 1 HR 2.03, Day 4 HR 2.77), independent of clinical factors.

Conclusions:

  • In vivo TLR4 activation in sepsis is a phenotype present in a specific high-risk subgroup.
  • Increased TLR4 activation is a strong predictor of mortality in sepsis.
  • Findings support a precision medicine approach for sepsis treatment, potentially explaining prior trial failures.
Keywords:
30-day-survivalEndotypePrecision medicineProximity ligation assaySepsisSepsisDataNet.NRWTLR4 phosphorylationTLR4 receptor

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