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Matrix Stiffness Regulates Interleukin-10 Secretion in Human Microglia (HMC3) via YAP-Mediated Mechanotransduction

Xue Fang1, Haiying Jia2, Shaoshan Pan1

  • 1CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics, University of Science and Technology of China, Hefei, China.

Cell Biochemistry and Function
|February 26, 2025
PubMed

Insights

Matrix stiffness regulates brain immune cell IL-10 secretion via YAP mechanotransduction. This pathway impacts glioma growth, offering new therapeutic targets for brain tumors.

Area of Science:

  • Neuroimmunology
  • Mechanobiology
  • Cellular Biology

Background:

  • Microglia, the brain's immune cells, interact with the extracellular matrix.
  • Understanding how matrix properties influence microglial function is crucial but limited.
  • The molecular mechanisms linking matrix stiffness to microglial cytokine secretion are not well-defined.

Purpose of the Study:

  • To investigate how extracellular matrix stiffness regulates interleukin-10 (IL-10) secretion in human microglia.
  • To elucidate the role of yes-associated protein (YAP)-mediated mechanotransduction in this process.
  • To explore the therapeutic potential of targeting YAP in microglia for glioma treatment.

Main Methods:

  • Culturing human microglia (HMC3) on hydrogels of varying stiffness.
  • Assessing IL-10 secretion levels.
  • Analyzing the expression and nuclear localization of YAP.
  • Performing YAP depletion and overexpression experiments.
  • Evaluating the impact of YAP silencing on microglial proliferation and glioma growth.

Main Results:

  • Soft substrates reduced IL-10 secretion and YAP nuclear localization, while stiffer substrates increased them.
  • YAP depletion suppressed IL-10 secretion, indicating YAP's necessity.
  • Cytoskeletal polymerization was identified as critical for YAP-mediated IL-10 regulation.
  • Silencing YAP in microglia reduced their pro-proliferative effect on gliomas and weakened microglial contractility.

Conclusions:

  • Matrix stiffness controls microglial IL-10 secretion through YAP-dependent mechanotransduction.
  • YAP acts as a key sensor of matrix stiffness in microglia, influencing cytokine release.
  • Targeting YAP in microglia presents a potential therapeutic strategy for glioma.
Keywords:
HMC3glioma proliferationhuman microgliainterleukin‐10matrix stiffnessyes‐associated protein

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