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Updated: Oct 24, 2025
Author Spotlight: THP-1 Macrophage Response to LPS/ATP — Unveiling the Pyroptosis, Apoptosis, and Necroptosis Spectrum
Published on: May 3, 2024
Blockade of macrophage-associated programmed death 1 inhibits the pyroptosis signalling pathway in sepsis
Yang Fu1, Denian Wang2, Shuang Wang1
1Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
Objective:
Programmed death 1 (PD-1) and macrophages are the most intriguing candidates in sepsis-induced inflammatory disorders. We aimed to investigate the association between monocyte PD-1 and sepsis severity and the mechanism by which blocking macrophage-associated PD-1 causes inflammatory disorders in sepsis.
Materials And Methods:
We first measured whether the expression of PD-1 on the monocyte subset is clinically associated with sepsis severity in an observational study. This study included 42 septic patients and 16 healthy controls (HCs) whose serum inflammatory factors were examined by Luminex MagPix. Then, we investigated the effect of PD-1 blockade on macrophages from septic mice (C57BL/6 mice) constructed by caecal ligation and puncture (CLP) via RNA sequencing. The positive genes screened by RNA-seq were verified in LPS-stimulated RAW264.7 cells by Western blot.
Results:
The results showed that the expression of PD-1 on CD14+CD16+ monocytes (intermediate monocytes, IM Mo) was significantly higher in both septic and septic shock patients than in HCs. Further analysis of serum cytokines in septic patients showed that the levels of IL-6 and TNF-α were significantly higher than those in HCs, while serum PD-1 levels were decreased in septic patients. More interestingly, blockade of PD-1 on macrophages from septic mice suppressed the gene expression levels of NLRP3/Caspase-4/AKT2/STAT3. The protein levels associated with pyroptosis including NLRP3, Caspase4, GSDMD and NT-GSDMD were significantly decreased in LPS-stimulated RAW264.7 cells treated with PD-1 antibody.
Conclusion:
Our results suggested that intermediate monocytes with high expression of PD-1 may be involved in the progression of sepsis. PD-1 might play a critical role in regulating the pyroptosis signalling pathway in sepsis.
Insights
High programmed death 1 (PD-1) on intermediate monocytes correlates with sepsis severity. Blocking PD-1 in macrophages impacts sepsis-related inflammatory pathways, suggesting a role in disease progression.
Area of Science:
- Immunology
- Sepsis Pathophysiology
Background:
- Programmed death 1 (PD-1) and macrophages are implicated in sepsis-induced inflammation.
- The role of monocyte PD-1 in sepsis severity and its mechanistic impact on inflammation require further investigation.
Purpose of the Study:
- To investigate the association between monocyte PD-1 expression and sepsis severity.
- To elucidate the mechanism by which blocking macrophage-associated PD-1 influences sepsis-related inflammatory disorders.
Main Methods:
- Observational study of 42 septic patients and 16 healthy controls (HCs) measuring monocyte PD-1 and serum cytokines (Luminex MagPix).
- Investigated PD-1 blockade effects on macrophages from septic mice (CLP model) using RNA sequencing.
- Verified gene expression changes in LPS-stimulated RAW264.7 cells via Western blot.
Main Results:
- PD-1 expression was significantly higher on intermediate monocytes (CD14+CD16+) in septic patients compared to HCs.
- Septic patients exhibited elevated serum IL-6 and TNF-α, with decreased serum PD-1 levels.
- PD-1 blockade in septic mouse macrophages suppressed NLRP3/Caspase-4/AKT2/STAT3 gene expression and reduced pyroptosis-associated proteins in cell models.
Conclusions:
- High PD-1 expression on intermediate monocytes may contribute to sepsis progression.
- PD-1 plays a critical role in regulating the pyroptosis signaling pathway during sepsis.
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