PRC1 promotes immunosuppressive macrophages in sepsis via β-catenin/STAT3 signaling

Immunosuppression is a distinctive condition resulting from sepsis, marked by impaired immune response and immune dysregulation, with a poor prognosis. PRC1, a mitotic regulatory protein, is associated with immune suppression within the tumor microenvironment. However, the role of PRC1 in septic immunosuppression remains unclear. This research aimed to explore the implication and potential mechanism of PRC1 in septic immunosuppression.

Dataset GSE95233 and GSE65682 were used to validate the expression and prognostic value of PRC1 in sepsis patients. LPS was used to stimulate naïve or endotoxin-tolerant THP-1 and BMDMs. PRC1 expression was measured in by RT-qPCR and Western blot. Small interfering RNA was used for PRC1 knockdown in THP-1. The phosphorylated STAT3 and active β-catenin was detected by Western blot. The expression levels of cytokines and surface markers of macrophages were validated by RT-qPCR. β-catenin inhibitor MSAB and agonist SKL2001 were used to explore the functional relationship among relevant molecules.

PRC1 expression was increased in sepsis non-survivors in both dataset GSE95233 and GSE65682, and increased PRC1 expression was associated with increased 28-days septic mortality. PRC1 expression was elevated in endotoxin-tolerant macrophages rather than naïve macrophages. Sustained phosphorylation of STAT3 was detected in endotoxin-tolerant macrophages. Increased PRC1 expression maintained the phosphorylated STAT3 level via a β-catenin-dependent mechanism, which was reversed by β-catenin inhibitor MSAB. PRC1 knockdown could reduce STAT3 phosphorylation and restore inflammatory responses in endotoxin-tolerant macrophages, while this effect was eliminated by β-catenin agonist SKL2001. Septic microenvironment promoted the expression of PRC1 in endotoxin-tolerant macrophages.

Our data demonstrated that PRC1 is upregulated in endotoxin-tolerant macrophages, and that increased PRC1 expression maintains STAT3 activation via a β-catenin-dependent mechanism and impairs inflammatory response of macrophages during septic immunosuppression. Targeting PRC1/β-catenin/ STAT3 could represent a novel strategy for the management of septic immunosuppression and restore the inflammatory response of endotoxin-tolerant macrophages.