Suppression by apoptotic cells defines tumor necrosis factor-mediated induction of glomerular mesangial cell

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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

Published on: December 27, 2016

J S Duffield1, C F Ware, B Ryffel

  • 1Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom. j.duffield@ed.ac.uk

The American Journal of Pathology
|October 5, 2001
PubMed

Insights

Activated macrophages induce kidney cell death via tumor necrosis factor (TNF). This process is suppressed when macrophages engulf apoptotic cells, suggesting a new feedback loop in inflammation.

Area of Science:

  • Immunology
  • Nephrology
  • Cell Biology

Background:

  • Activated macrophages (M(phi)) in inflamed glomeruli can cause glomerular mesangial cell apoptosis.
  • The precise mechanisms underlying this M(phi)-induced apoptosis are not fully understood.

Purpose of the Study:

  • To elucidate the mechanisms of nitric oxide-independent mesangial cell apoptosis induced by activated M(phi).
  • To investigate the role of tumor necrosis factor (TNF) in this process.
  • To explore the regulatory role of apoptotic cell binding/ingestion by M(phi).

Main Methods:

  • Co-culture of activated M(phi) with mesangial cells.
  • Use of nitric oxide synthase inhibitors.
  • Treatment with soluble TNF receptor-1.
  • Experiments with murine TNF knockout M(phi).

Main Results:

  • Nitric oxide-independent mesangial cell apoptosis was mediated by TNF.
  • Soluble TNF receptor-1 significantly inhibited M(phi)-induced apoptosis when nitric oxide release was minimal.
  • Murine TNF knockout M(phi) failed to induce mesangial cell apoptosis under conditions of inhibited nitric oxide synthesis.
  • Binding/ingestion of apoptotic cells by M(phi) suppressed TNF-mediated mesangial cell apoptosis.

Conclusions:

  • Tumor necrosis factor (TNF) is a key mediator of M(phi)-induced glomerular mesangial cell apoptosis, independent of nitric oxide.
  • Macrophage engulfment of apoptotic cells acts as a negative feedback mechanism, down-regulating M(phi)-driven apoptosis.
  • This suggests a novel regulatory pathway controlling resident cell numbers at sites of inflammation.

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