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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

Different signaling pathways stimulate a disintegrin and metalloprotease-17 (ADAM17) in neutrophils during apoptosis

Yue Wang1, John D Robertson, Bruce Walcheck

  • 1Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota 55108, USA.

The Journal of Biological Chemistry
|September 28, 2011
PubMed

Insights

This study reveals the signaling pathway activating ADAM17 protease during neutrophil apoptosis, involving caspase-8 and mitochondrial reactive oxygen species. This process reduces neutrophil inflammatory responses by shedding TNF receptors.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • ADAM17 is a metalloprotease on neutrophil surfaces, regulating receptor density.
  • ADAM17 activity is inducible upon neutrophil activation and apoptosis.
  • The specific signaling pathway for ADAM17 induction during neutrophil apoptosis remains largely unknown.

Purpose of the Study:

  • To elucidate the signal transduction pathway that stimulates ADAM17 activity during induced neutrophil apoptosis.
  • To differentiate the apoptotic pathway from the pathway activated during overt neutrophil activation.

Main Methods:

  • Investigated the role of caspase-8, Bid cleavage, and mitochondrial reactive oxygen species in Fas signaling.
  • Compared signaling requirements for ADAM17 activation in apoptosis versus overt activation (MAPK p38/ERK).
  • Assessed shedding of TNF receptors (TNF-RI, TNF-RII) as ADAM17 substrates during apoptosis.

Main Results:

  • Caspase-8 activation, Bid cleavage, and mitochondrial reactive oxygen species release are sequential steps in Fas-induced ADAM17 signaling during apoptosis.
  • This apoptotic pathway differs from overt activation, which relies on MAPK p38 or ERK, not caspases or ROS.
  • ADAM17 sheds TNF-RI and TNF-RII during neutrophil apoptosis, reducing sensitivity to TNFα.

Conclusions:

  • Identified a novel signal transduction pathway for ADAM17 activation during neutrophil apoptosis.
  • ADAM17 induction during apoptosis may attenuate neutrophil pro-inflammatory activity by decreasing sensitivity to TNFα.
  • This mechanism contributes to inflammation resolution by modulating neutrophil inflammatory functions.

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