Editors' ChoiceImmunology

Avoiding Inflammation During Apoptosis

Sci. Signal.  01 Apr 2014:
Vol. 7, Issue 319, pp. ec89
DOI: 10.1126/scisignal.2005314

Cells undergoing apoptosis or necrosis are engulfed by macrophages. Whereas cells undergoing necrotic death rupture and release factors that stimulate inflammation, cells dying by apoptosis remain intact and actively suppress inflammation. Yamaguchi et al. found that the expression of anti-inflammatory genes in mouse bone marrow–derived macrophage (BMDMs) was induced by application of culture medium conditioned by apoptotic mouse W3 cells, but not from nonapoptotic cells. The authors identified adenosine monophosphate (AMP) as the soluble factor responsible for this activity. Ecto-5′-nucleotidases convert AMP to adenosine and are present on the surface of macrophages. Inhibiting these enzymes prevented the anti-inflammatory transcriptional response in BMDMs treated with supernatant from apoptotic W3 cells. BMDMs from mice lacking the A2a adenosine receptor also failed to initiate the anti-inflammatory transcriptional response upon treatment with apoptotic cell supernatant. Pannexins are membrane channels that mediate the release of adenine nucleotides (ATP, ADP, and AMP), and their activity is stimulated by caspase-mediated cleavage. Overexpression of Pannexin 1 increased the release of adenine nucleotides from apoptotic W3 cells, and application of a Pannexin inhibitor reduced adenine release. Expression of a form of Pannexin 1 that could not be cleaved by caspases inhibited release of adenine nucleotides from apoptotic W3 cells and prevented the anti-inflammatory transcriptional response of BMDMs cocultured with apoptotic W3 cells. Finally, mice lacking Panx1 or A2a showed prolonged inflammation when subjected to zymosan-induced peritonitis compared with wild-type mice. Thus, AMP released by apoptotic cells is converted to adenosine by macrophages and suppresses the inflammatory response in macrophages through activation of the A2a adenosine receptor. These findings add AMP to the complex mixture of soluble and cell surface–associated molecules that are released by or displayed on apoptotic cells to help phagocytes find and engulf them (see commentary by Wallach and Kovalenko) without triggering inflammation.

H. Yamaguchi, T. Maruyama, Y. Urade, S. Nagata, Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells. eLIFE 3, e02172 (2014). [Online Journal]

D. Wallach, A. Kovalenko, Apoptosis: Keeping inflammation at bay. eLIFE 3, e02583 (2014). [Online Journal]