Fucosylated haptoglobin promotes inflammation via Mincle in sepsis: an observational study.

Summary

This translational study links site-specific fucosylation of haptoglobin to augmented inflammation in sepsis via the C-type lectin receptor Mincle. The authors integrate human plasma glycoproteomics, single-cell RNA-seq, receptor interaction assays, and in vivo mouse validation, positioning fucosylated haptoglobin as a clinically relevant biomarker and potential therapeutic target.

Key Findings

• Terminal fucosylation at Hp Asn207/Asn211 was elevated in sepsis patient plasma and correlated with inflammatory cytokine levels (AAL signal association).
• Fu-Hp induced cytokines/chemokines and NLRP3 inflammasome activation; scRNA-seq revealed a macrophage-like population with increased inflammatory mediators and FUT4 in response to Fu-Hp.
• Mincle directly interacted with Fu-Hp to amplify signaling; Fu-Hp administration increased inflammatory cytokines in plasma and tissues of mice.

Clinical Implications

Assays quantifying Hp fucosylation could aid risk stratification and monitoring of inflammatory burden in sepsis. Therapeutic strategies targeting Fu-Hp–Mincle interactions (e.g., lectin blockade or glycosylation modulation) merit exploration.

Limitations

• Observational human data limit causal inference; sample size and cohort characteristics are not detailed in the abstract.
• Generalizability across sepsis etiologies and care settings requires external validation; glycan-specific assays may face standardization challenges.

Future Directions

Prospective validation of Hp fucosylation as a prognostic biomarker; mechanistic and preclinical testing of Mincle blockade or glycosylation modulation; development of clinical-grade assays for Fu-Hp quantification.