@article{1828ec825b5c4dd39e7f6bb46f690fa6,
title = "Necrosis-Driven Systemic Immune Response Alters SAM Metabolism through the FOXO-GNMT Axis",
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.",
author = "Fumiaki Obata and Erina Kuranaga and Katsura Tomioka and Ming Ming and Asuka Takeishi and Chen, {Chun Hong} and Tomoyoshi Soga and Masayuki Miura",
note = "Funding Information: We are grateful to Y. Imai (Musashino University) for advice on the UPLC analysis. We thank Y. Imai (Juntendo University), T. Nishimura, A. Gould, P. Leopold, S. Pletcher, G. Rubin, L. Patridge, A. Bergmann, D.J. Pan, S. Kurata, B. Lemaitre, J.L. Imler, J.M. Abrams, C. Thummel, E. Hafen, N. Perrimon, B. Edgar, the Vienna Drosophila RNAi Center, and the Bloomington Drosophila Stock Center for Drosophila stocks and antibodies. We thank T. Chihara, Y. Yamaguchi, L. Zhang, S. Kashio, T. Yamazaki, K. Takeuchi, S. Haraguchi, K. Takenaga, M. Sasaki, A. Isomura, A. Tsukioka, and Y. Fujioka for technical assistance and discussions. This work was supported by grants from the Japanese Ministry of Education, Science, Sports, Culture, and Technology (to M. Miura and E.K.) and the Uehara Memorial Foundation (to E.K.). F.O. and A.T. are research fellows of the Japan Society for the Promotion of Science. ",
year = "2014",
doi = "10.1016/j.celrep.2014.03.046",
language = "English",
volume = "7",
pages = "821--833",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}