Metrnβ drives sepsis immunosuppression via macrophage reprogramming: A novel prognostic biomarker and therapeutic target
Xiao Li, Ai Chen, Chen Zhang, Meihong Da, Yonghui Liu, Zhi He, Chenyan Yuan, Shuo Ma, Yuming Yao, Dawen Chen, Meiling Zhou, Zhixin Song, Wenjing Lu, Chun‐Kwok Wong, Guoqiu Wu, Xun GaoAbstract
Sepsis is a heterogeneous syndrome critically driven by immunosuppression, yet lacking personalized prognostic markers and therapeutic targets. Here, we provide evidence to support Metrnβ as a novel prognostic biomarker in sepsis mortality and the function of Metrnβ in modulating macrophage polarization during sepsis immunosuppression. Metrnβ is significantly elevated at disease onset in three independent cohorts comprising adult and pediatric septic patients, and maintained a strong association with 28‐day mortality. In murine sepsis, Metrnβ expression was markedly upregulated in peripheral blood, peritoneal lavage fluid, and various organs, exhibiting macrophage‐specific co‐localization; specific depletion of macrophages reduced systemic Metrnβ levels in vivo. Administration of recombinant murine Metrnβ (rmMetrnβ) aggravated mortality of septic mice in a dose‐dependent manner, whereas genetic ablation or neutralization of Metrnβ improved survival by restoring proinflammatory responses and enhancing bacterial clearance. Mechanistically, single‐cell RNA sequencing and bulk RNA‐seq revealed that Metrnβ orchestrated immune collapse by driving macrophage reprogramming toward an immunosuppressive phenotype. Critically, the adverse effects of Metrnβ in sepsis were mediated through its interaction with c‐Kit on macrophages. Collectively, our findings establish Metrnβ as a key prognostic biomarker and validate the targeted blockade of the Metrnβ‐c‐Kit axis as an effective therapeutic approach for immunocompromised sepsis.