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

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Isoflurane promotes phagocytosis of apoptotic neutrophils through AMPK-mediated ADAM17/Mer signaling

Xueke Du1,2, Chunling Jiang1, Yang Lv1

  • 1Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois, United States of America.

Plos One
|July 4, 2017
PubMed

Insights

Isoflurane enhances macrophage efferocytosis, promoting resolution of lung inflammatory injury. This involves increased Mer receptor expression via AMPK-mediated inhibition of ADAM17, aiding neutrophil clearance and tissue repair.

Area of Science:

  • Immunology
  • Anesthesiology
  • Cell Biology

Background:

  • Resolution of inflammation and tissue repair are crucial for recovery from lung injury.
  • Macrophage efferocytosis, the clearance of apoptotic neutrophils, is vital for resolving inflammation.
  • The role of anesthetics like isoflurane in modulating efferocytosis and inflammation resolution is not well understood.

Purpose of the Study:

  • To investigate the effects of isoflurane on macrophage efferocytosis.
  • To determine if isoflurane can promote the resolution of lung inflammatory injury.
  • To elucidate the molecular mechanisms underlying isoflurane's effects on efferocytosis.

Main Methods:

  • Murine bone marrow-derived macrophages (BMDMs) and alveolar macrophages were treated with isoflurane.
  • Phagocytosis of apoptotic neutrophils by macrophages was assessed.
  • Surface expression of Mer receptor and ADAM17, and levels of soluble Mer, were measured.
  • AMPK pathway involvement was investigated using inhibitors and genetic deletion.
  • A mouse model of lipopolysaccharide (LPS)-induced lung injury was used to evaluate in vivo effects.

Main Results:

  • Isoflurane significantly enhanced macrophage phagocytosis of apoptotic neutrophils.
  • Isoflurane increased surface Mer receptor expression and decreased soluble Mer.
  • Isoflurane reduced cell surface ADAM17 while increasing its cytoplasmic fraction.
  • These effects were dependent on AMP-activated protein kinase (AMPK) activation.
  • In vivo, isoflurane accelerated recovery from LPS-induced lung injury, correlating with increased efferocytosis.

Conclusions:

  • Isoflurane promotes the resolution of lung inflammatory injury by enhancing macrophage efferocytosis.
  • This enhancement is mediated by the upregulation of Mer surface expression through AMPK-dependent inhibition of ADAM17 trafficking.
  • Isoflurane represents a potential therapeutic strategy for managing inflammatory lung conditions.

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