CREG1 mitigates sepsis-induced acute lung injury by mediating macrophage polarization via AMPK/NF-κB signaling

Sepsis-induced acute lung injury (ALI) is a severe respiratory disease that usually progresses to acute respiratory distress syndrome (ARDS). Cellular repressor of E1A-stimulated genes 1 (CREG1), a secreted glycoprotein, participates in tissue homeostasis, influences inflammation, and improves cardiovascular functions. In this study, we aimed to investigate the diagnostic role and mechanism of CREG1 in sepsis-induced ALI.

Serum samples from 88 patients with sepsis and 20 healthy individuals were collected. Serum CREG1 levels were detected. The correlations between CREG1 levels and patient survival rates, inflammatory mediator levels, SOFA scores, and APACHE II scores were analyzed. ROC curve analysis and the KaplanMeier method were used to evaluate the associations between CREG1 levels and 28-day mortality. A sepsis-induced ALI model was established in C57BL/6J mice via cecal ligation and puncture (CLP) surgery. The CLP mice were treated with recombinant CREG1 protein (rCREG1), and alterations in lung injury, macrophage polarization, inflammation, and oxidative stress levels were examined.

Compared with healthy controls, patients with sepsis had higher CREG1 levels. ROC curve analysis revealed that the CREG1 level had an AUC of 0.6245 and that the SOFA score had an AUC of 0.8323 for predicting 28-day mortality. Decreased CREG1 levels were detected in nonsurviving patients and were significantly associated with poor prognosis. Treatment with rCREG1 significantly improved inflammation and oxidative stress in the lungs of CLP model mice and promoted the "M1" to "M2" polarization of macrophages. Mechanistically, rCREG1 enhanced the activation of AMPK and suppressed the phosphorylation of NF-κB p65.

Serum CREG1 levels were altered and associated with the survival of patients with sepsis-induced ALI. Treatment with rCREG1 alleviated the progression of sepsis-induced ALI by regulating macrophage polarization and the AMPK/NF-κB pathway. These findings suggest that CREG1 is a potential prognostic candidate biomarker, but its clinical utility requires further validation in multicenter cohorts and female populations.