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Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity
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Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity

Published on: October 17, 2025

Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging

Yuting Jessy Tan1, Travis E Conley1, Fuwen Yao1

  • 1Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Science (New York, N.Y.)
|July 16, 2026
PubMed

Insights

Aging impairs tissue repair by affecting tissue-resident macrophages (TRMs). Targeting the EP2 receptor on TRMs can restore youthful function and prevent age-related organ decline.

Area of Science:

  • Immunology
  • Aging research
  • Cellular biology

Background:

  • Aging disrupts tissue homeostasis and organ function.
  • Tissue-resident macrophages (TRMs) play a role in age-related decline.
  • Impaired clearance of senescent neutrophils contributes to aging.
  • Prostaglandin E2 (PGE2) receptor EP2 signaling is implicated in this process.

Purpose of the Study:

  • To investigate the role of TRM EP2 signaling in age-related organ decline.
  • To determine if modulating TRM EP2 signaling can reverse aging phenotypes.

Main Methods:

  • Studied aged mice with reduced TRM EP2 signaling.
  • Analyzed neutrophil efferocytosis and mitochondrial fitness.
  • Utilized plasma proteomics to identify liver involvement.
  • Examined aged and diseased human tissues for EP2 expression and senescent neutrophils.
  • Tested pharmacologic EP2 inhibition.

Main Results:

  • Reducing TRM EP2 signaling in aged mice preserved mitochondrial fitness and prevented multiple age-related conditions.
  • This intervention improved neutrophil efferocytosis and reduced cellular stress in the liver.
  • Elevated TRM EP2 expression and senescent neutrophils were found in aged human tissues.
  • Pharmacologic EP2 inhibition restored youthful neutrophil clearance.

Conclusions:

  • Impaired TRM efferocytosis of senescent neutrophils, driven by EP2 signaling, is a reversible cause of organ decline in aging.
  • Targeting TRM EP2 signaling offers a potential therapeutic strategy for age-related diseases.

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