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Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages.

Publication ,  Journal Article
Schmidt, EA; Fee, BE; Henry, SC; Nichols, AG; Shinohara, ML; Rathmell, JC; MacIver, NJ; Coers, J; Ilkayeva, OR; Koves, TR; Taylor, GA
Published in: J Biol Chem
March 17, 2017

The immunity-related GTPases (IRGs) are a family of proteins that are induced by interferon (IFN)-γ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear. In the studies reported here, we found that uninfected Irgm1-deficient mice displayed high levels of serum cytokines typifying profound autoinflammation. Similar increases in cytokine production were also seen in cultured, IFN-γ-primed macrophages that lacked Irgm1. A series of metabolic studies indicated that the enhanced cytokine production was associated with marked metabolic changes in the Irgm1-deficient macrophages, including increased glycolysis and an accumulation of long chain acylcarnitines. Cells were exposed to the glycolytic inhibitor, 2-deoxyglucose, or fatty acid synthase inhibitors to perturb the metabolic alterations, which resulted in dampening of the excessive cytokine production. These results suggest that Irgm1 deficiency drives metabolic dysfunction in macrophages in a manner that is cell-autonomous and independent of infectious triggers. This may be a significant contributor to excessive inflammation seen in Irgm1-deficient mice in different contexts.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

March 17, 2017

Volume

292

Issue

11

Start / End Page

4651 / 4662

Location

United States

Related Subject Headings

  • Mice
  • Macrophages
  • Interferon-gamma
  • Inflammation
  • Glycolysis
  • Gene Deletion
  • GTP-Binding Proteins
  • Cytokines
  • Cells, Cultured
  • Biochemistry & Molecular Biology
 

Citation

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Schmidt, E. A., Fee, B. E., Henry, S. C., Nichols, A. G., Shinohara, M. L., Rathmell, J. C., … Taylor, G. A. (2017). Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages. J Biol Chem, 292(11), 4651–4662. https://doi.org/10.1074/jbc.M116.770735
Schmidt, Elyse A., Brian E. Fee, Stanley C. Henry, Amanda G. Nichols, Mari L. Shinohara, Jeffrey C. Rathmell, Nancie J. MacIver, et al. “Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages.J Biol Chem 292, no. 11 (March 17, 2017): 4651–62. https://doi.org/10.1074/jbc.M116.770735.
Schmidt EA, Fee BE, Henry SC, Nichols AG, Shinohara ML, Rathmell JC, et al. Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages. J Biol Chem. 2017 Mar 17;292(11):4651–62.
Schmidt, Elyse A., et al. “Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages.J Biol Chem, vol. 292, no. 11, Mar. 2017, pp. 4651–62. Pubmed, doi:10.1074/jbc.M116.770735.
Schmidt EA, Fee BE, Henry SC, Nichols AG, Shinohara ML, Rathmell JC, MacIver NJ, Coers J, Ilkayeva OR, Koves TR, Taylor GA. Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages. J Biol Chem. 2017 Mar 17;292(11):4651–4662.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

March 17, 2017

Volume

292

Issue

11

Start / End Page

4651 / 4662

Location

United States

Related Subject Headings

  • Mice
  • Macrophages
  • Interferon-gamma
  • Inflammation
  • Glycolysis
  • Gene Deletion
  • GTP-Binding Proteins
  • Cytokines
  • Cells, Cultured
  • Biochemistry & Molecular Biology