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Published on: May 31, 2018
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.
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.
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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