PTEN negatively regulates engulfment of apoptotic cells by modulating activation of Rac GTPase

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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Subhanjan Mondal1, Saurabh Ghosh-Roy, Fabien Loison

  • 1Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|November 2, 2011
PubMed

Insights

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulates efferocytosis, the process of clearing apoptotic cells. PTEN depletion enhances this crucial immune function and promotes an anti-inflammatory response.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Efficient clearance of apoptotic cells (efferocytosis) is vital for tissue homeostasis and immune regulation.
  • Macrophage receptors trigger phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] signaling for cytoskeletal changes during efferocytosis.
  • The role of lipid phosphatases, like PTEN, in efferocytosis remains largely unexplored.

Purpose of the Study:

  • To investigate the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in the process of efferocytosis.
  • To elucidate how PTEN activity influences macrophage phagocytic capabilities and downstream signaling pathways.

Main Methods:

  • Assessed PTEN activity in macrophages during efferocytosis.
  • Utilized PTEN depletion and overexpression in macrophages for in vitro and in vivo studies.
  • Analyzed downstream signaling molecules including PtdIns(3,4,5)P(3), Vav1, Rac1 GTPase, and F-actin.
  • Quantified cytokine production (IL-10, IL-6, TNF-α) following efferocytosis.

Main Results:

  • PTEN activity was found to be elevated during efferocytosis.
  • Depletion of PTEN enhanced PtdIns(3,4,5)P(3) production and improved macrophage phagocytic ability.
  • PTEN loss activated Vav1 and Rac1 GTPase, leading to increased F-actin and enhanced engulfment.
  • PTEN disruption promoted anti-inflammatory IL-10 production while reducing pro-inflammatory IL-6 and TNF-α.

Conclusions:

  • PTEN plays a critical regulatory role in efferocytosis by modulating PtdIns(3,4,5)P(3) levels.
  • PTEN influences cytoskeletal reorganization via Vav1 and Rac1 GTPase pathways.
  • PTEN activity impacts the inflammatory response during apoptotic cell clearance, favoring an anti-inflammatory state.

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