Kallikrein-related peptidase 8 mediates surgical stress-induced macrophage dysfunction and phagocytic defect via the

Qing Hua1, Yuting Yao2, Xintong Shi3

  • 1Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

Life Sciences
|July 11, 2026
PubMed
Abstract

Insights

Surgical stress increases KLK8, promoting CD206+ macrophages and impairing immune function. Targeting KLK8 may restore postoperative recovery by modulating the ER stress/CD44 pathway.

Area of Science:

  • Immunology
  • Molecular Biology
  • Surgical Science

Background:

  • Surgical stress alters immune cell populations, increasing infection risk and hindering recovery.
  • The precise molecular mechanisms behind these immune dysregulations remain unclear.

Purpose of the Study:

  • To investigate the role of monocyte/macrophage reprogramming in postoperative immune dysfunction.
  • To identify molecular pathways regulating macrophage function after surgery.

Main Methods:

  • Flow cytometry was used to analyze perioperative monocyte/macrophage polarization and phagocytosis in vitro and in vivo.
  • Bioinformatic and mechanistic analyses elucidated molecular pathways involved.
  • KLK8 function was assessed in KLK8-flox mice, and CD44 interaction was studied using co-immunoprecipitation and mass spectrometry.

Main Results:

  • Postoperative day 3 showed increased CD206 expression and impaired phagocytosis in monocytes/macrophages.
  • Kallikrein-related peptidase 8 (KLK8) was identified as a novel regulator, enhancing CD206 expression and suppressing phagocytosis.
  • KLK8 was found to directly cleave CD44, activating endoplasmic reticulum stress (ERS) signaling, which was partially reversed by ERS inhibition or CD44 agonism.

Conclusions:

  • Surgical stress upregulates KLK8, leading to CD206+ macrophage expansion and phagocytic dysfunction.
  • The KLK8-driven pathway involves endoplasmic reticulum stress and CD44.
  • KLK8 represents a potential therapeutic target for improving postoperative immune function.

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