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Updated: Jul 15, 2026

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

Apoptotic cells induce arginase II in macrophages, thereby attenuating NO production

Axel M Johann1, Vera Barra, Anne-Marie Kuhn

  • 1Johann Wolfgang Goethe-University, Faculty of Medicine, Institute of Biochemistry I, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|April 26, 2007
PubMed

Insights

Removal of apoptotic cells (AC) reduces nitric oxide (NO) production in macrophages by up-regulating arginase II. This mechanism involves a soluble lipid factor released by AC, impacting innate immune regulation.

Area of Science:

  • Immunology
  • Cell Biology

Background:

  • Phagocytosis of apoptotic cells (AC) by macrophages alters their phenotype, reducing pro-inflammatory cytokine and nitric oxide (NO) production.
  • The underlying molecular mechanisms for this suppressed NO formation have remained unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms responsible for reduced NO formation in macrophages upon exposure to AC.
  • To elucidate how AC influence macrophage function and innate immune responses.

Main Methods:

  • Stimulation of murine RAW264.7 macrophages with AC, necrotic, or viable cells.
  • Measurement of NO production and inducible nitric oxide synthase (iNOS) expression.
  • Analysis of arginase activity using radioactive L-arginine/citrulline conversion assay.
  • Gene expression analysis (RT-PCR, Western blot, luciferase reporter assays) and arginase II knockdown via siRNA.
  • Experiments using AC-conditioned medium to identify soluble factors.

Main Results:

  • AC exposure significantly reduced NO production in IFNgamma-stimulated macrophages, despite sustained iNOS expression.
  • Increased arginase activity, specifically arginase II, was observed in macrophages exposed to AC.
  • Inhibition or knockdown of arginase II restored NO production.
  • A soluble lipid factor from AC, not the act of phagocytosis itself, was identified as the modulator of NO production.

Conclusions:

  • Apoptotic cells release a lipid factor that up-regulates arginase II in macrophages.
  • Arginase II activation by this lipid factor leads to suppressed NO formation.
  • This pathway represents a novel mechanism for innate immune regulation by apoptotic cells.

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