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Cell Rep. 2014 May 8;7(3):821-33. doi: 10.1016/j.celrep.2014.03.046. Epub 2014 Apr 17.

Necrosis-driven systemic immune response alters SAM metabolism through the FOXO-GNMT axis.

Author information

1
Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan.
2
Laboratory for Histogenetic Dynamics, RIKEN CDB, Kobe 650-0047, Japan.
3
Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
4
National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
5
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.
6
Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan. Electronic address: miura@mol.f.u-tokyo.ac.jp.

Abstract

Sterile inflammation triggered by endogenous factors is thought to contribute to the pathogenesis of acute and chronic inflammatory diseases. Here, we demonstrate that apoptosis-deficient mutants spontaneously develop a necrosis-driven systemic immune response in Drosophila and provide an in vivo model for studying the organismal response to sterile inflammation. Metabolomic analysis of hemolymph from apoptosis-deficient mutants revealed increased sarcosine and reduced S-adenosyl-methionine (SAM) levels due to glycine N-methyltransferase (Gnmt) upregulation. We showed that Gnmt was elevated in response to Toll activation induced by the local necrosis of wing epidermal cells. Necrosis-driven inflammatory conditions induced dFoxO hyperactivation, leading to an energy-wasting phenotype. Gnmt was cell-autonomously upregulated by dFoxO in the fat body as a possible rheostat for controlling energy loss, which functioned during fasting as well as inflammatory conditions. We propose that the dFoxO-Gnmt axis is essential for the maintenance of organismal SAM metabolism and energy homeostasis.

PMID:
24746817
DOI:
10.1016/j.celrep.2014.03.046
[Indexed for MEDLINE]
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