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Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells

Hiroshi Yamaguchi1, Toshihiko Maruyama, Yoshihiro Urade

  • 1Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Elife
|March 27, 2014
PubMed

Insights

Apoptotic cells release adenosine monophosphate (AMP) which is converted to adenosine. This adenosine acts as a

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Apoptosis, or programmed cell death, normally occurs without inflammation.
  • The molecular mechanisms preventing inflammation during apoptosis are not fully understood.
  • Macrophages engulf apoptotic cells, but the process is anti-inflammatory.

Purpose of the Study:

  • To investigate the molecular mechanisms by which apoptosis remains an anti-inflammatory process.
  • To identify signaling molecules released by apoptotic cells that modulate macrophage activity.

Main Methods:

  • Analysis of macrophage gene expression in response to apoptotic cell supernatant.
  • Measurement of adenosine monophosphate (AMP) levels in apoptotic cell supernatant.
  • Use of inhibitors for nucleotidases and adenosine receptors.
  • Assessment of inflammatory mediator levels in knockout mice (Adora2a-/- or Panx1-/-) after zymosan injection.

Main Results:

  • Apoptotic cell supernatant induced anti-inflammatory gene expression (Nr4a, Thbs1) in macrophages.
  • High levels of AMP were found in apoptotic cell supernatant, dependent on Pannexin1 (Panx1).
  • Inhibition of nucleotidases or A2a adenosine receptor blocked the anti-inflammatory gene induction.
  • AMP is metabolized to adenosine by macrophages, activating the A2a adenosine receptor.
  • Mice deficient in Adora2a or Panx1 exhibited sustained inflammatory responses.

Conclusions:

  • Adenosine monophosphate (AMP) released from apoptotic cells acts as an anti-inflammatory signal.
  • This 'calm down' signal is mediated by macrophage ecto-5'-nucleotidase conversion of AMP to adenosine, activating the A2a adenosine receptor.
  • Pannexin1 and the adenosine pathway are crucial for suppressing inflammation during cell death.
Keywords:
adenosine receptorsapoptosisinflammationmacrophage

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