Kallikrein-related peptidase 8 mediates surgical stress-induced macrophage dysfunction and phagocytic defect via the CD44/ERS axis.

AIMS: Surgical stress reprograms monocyte/macrophage populations, rendering patients more susceptible to infections and impairing postoperative recovery. However, the underlying mechanisms remain incompletely understood.

MATERIALS AND

METHODS

Using flow cytometry, we systematically characterized perioperative monocyte/macrophage polarization and phagocytic function in both in vitro and in vivo models, followed by integrated bioinformatic and mechanistic analyses to elucidate the molecular pathways involved.

KEY FINDINGS: On postoperative day 3, we observed a marked increase in CD206 expression (suggestive of a reparative/alternative phenotype) in monocytes/macrophages, accompanied by impaired phagocytic function. Through systematic screening, kallikrein-related peptidase 8 (KLK8) was identified as a novel regulator of macrophage functional states. Elevated KLK8 enhanced CD206 expression while suppressing phagocytic activity, and these effects were partially abrogated in KLK8-flox mice following KLK8 deletion. To investigate the underlying molecular pathways, co-immunoprecipitation coupled with mass spectrometry identified CD44 as a direct substrate of KLK8 in macrophages. Gene set enrichment analysis (GSEA) revealed significant enrichment of unfolded protein response (UPR) pathways in KLK8-modulated macrophages. Subsequent validation confirmed that KLK8 activates endoplasmic reticulum stress (ERS) signaling in RAW264.7 cells. Pharmacological inhibition of ERS partially rescued KLK8-mediated effects, whereas CD44 agonism effectively counteracted KLK8-induced ERS activation.

SIGNIFICANCE: Collectively, these findings demonstrate that surgical stress-induced KLK8 upregulation drives CD206+ macrophage expansion and phagocytic dysfunction via the ERS/CD44 axis, implicating KLK8 as a potential therapeutic target for restoring postoperative immune function.