Exploring METRNL as a novel biomarker in sepsis: diagnostic potential and secretion mechanism.

Background: Sepsis is a life-threatening condition with a high mortality rate in intensive care unit (ICU). However, rapid and accurate diagnostic criteria are still lacking. This pilot study explored the role of METRNL as a novel biomarker for sepsis by focusing on its diagnostic potential and rapid secretion mechanism.

Methods: METRNL levels were measured in cell and animal models of sepsis. Serum samples from 107 sepsis patients and 95 non-septic controls in ICU were collected. Diagnostic performance of METRNL, Procalcitonin (PCT) and C-reactive protein (CRP) were assessed using ROC analysis. Endothelial cell-specific Metrnl gene knockout mice (EC-Metrnl^-/- mice) were used to identify the source of METRNL secretion. Chemical inhibitors and RNA interference were used to explore the secretion pathways.

Results: In lipopolysaccharide (LPS)-induced cell and mouse models of sepsis, METRNL levels significantly increased in a dose- and time-dependent manner. Similarly, in the cecal ligation and puncture mouse models, serum METRNL levels were elevated over time and correlated with sepsis severity. In animals, serum METRNL increased within 1 h post-modeling, preceding PCT and CRP. Clinically, sepsis patients had significantly higher serum METRNL levels. ROC analysis showed area under the curves [95% confidence intervals] of 0.943 [0.91-0.975] for METRNL, 0.955 [0.929-0.981] for PCT and 0.873 [0.825-0.921] for CRP. At the optimal cutoff value, METRNL (91.6%) exhibited relatively greater diagnostic specificity than PCT (88.4%) and CRP (69.5%). EC-Metrnl^-/- reduced majority of serum Metrnl levels in sepsis mouse models. Inhibition of the endoplasmic reticulum-Golgi (ER-Golgi) pathway through chemical inhibitors or RNA interference significantly reduced METRNL levels in the supernatant of sepsis cell models compared to control groups. Similar results were obtained with Toll-like receptor 4 (TLR4) and ERK inhibitors.

Conclusions: This pilot study demonstrates that METRNL is a novel potential biomarker for sepsis with diagnostic capability comparable to that of PCT. Serum METRNL rapidly increased during the early phase of sepsis. Mechanistically, it mainly originates from the endothelium during sepsis, and TLR4-ERK signaling mediates the rapid secretion of METRNL via the classical ER-Golgi pathway in response to LPS stimulation.