Genetic and Experimental Evidence Implicates CCL4 in Severe Sepsis Risk and Phase-Dependent Immune Dynamics

Area of Science:

• Genetics
• Immunology
• Sepsis Pathogenesis

Background:

• Inflammatory cytokines are crucial in sepsis, but their causal roles are hard to determine due to biases.
• Mendelian randomization (MR) can investigate genetically determined cytokine levels in sepsis risk.
• Translational validation in clinical cohorts and experimental models is essential.

Purpose of the Study:

• To investigate the causal role of genetically determined cytokine levels in sepsis risk using MR.
• To validate findings in clinical cohorts and experimental models.
• To explore the dynamic changes of identified cytokines in sepsis progression.

Main Methods:

• Integrated cis-protein quantitative trait loci (cis-pQTL) of plasma cytokines with UK Biobank sepsis GWAS.
• Employed inverse-variance weighted MR, Wald ratio methods, and sensitivity analyses.
• Validated findings in severe sepsis patients and a cecal ligation and puncture (CLP) rat model.

Main Results:

• Genetically elevated Chemokine CC motif ligand 4 (CCL4) levels were associated with critical sepsis risk.
• Septic patients showed higher peripheral blood CCL4 levels within 24 hours compared to controls.
• CCL4 levels peaked early and declined later in a rat model, correlating with T-cell exhaustion markers.

Conclusions:

• CCL4 dynamics exhibit distinct phases in sepsis: early elevation (hyperinflammation) and later decline (T-cell exhaustion).
• CCL4 monitoring may serve as a biomarker for immunophenotype stratification in sepsis.
• Understanding CCL4 trajectory is relevant for developing time-sensitive therapeutic strategies.