Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages.
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.
From the Departments of Molecular Genetics and Microbiology.
Elyse A
EA
Schmidt
the Geriatric Research, Education, and Clinical Center, Durham Veterans Affairs Health Care System, Durham, North Carolina 27705, and.
Brian E
BE
Fee
the Geriatric Research, Education, and Clinical Center, Durham Veterans Affairs Health Care System, Durham, North Carolina 27705, and.
Stanley C
SC
Henry
the Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes.
Amanda G
AG
Nichols
From the Departments of Molecular Genetics and Microbiology.|the Department of Immunology.
Mari L
ML
Shinohara
the Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, Tennessee 37232.
Jeffrey C
JC
Rathmell
the Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes.
Nancie J
NJ
MacIver
From the Departments of Molecular Genetics and Microbiology.
Jörn
J
Coers
the Duke Molecular Physiology Institute, and.
Olga R
OR
Ilkayeva
the Duke Molecular Physiology Institute, and.|the Department of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina 27710.
Timothy R
TR
Koves
From the Departments of Molecular Genetics and Microbiology, gregory.taylor@duke.edu.|the Geriatric Research, Education, and Clinical Center, Durham Veterans Affairs Health Care System, Durham, North Carolina 27705, and.|the Department of Immunology.|the Department of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina 27710.
Gregory A
GA
Taylor
D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000276:immunology; D017353:Gene Deletion; D006019:Glycolysis; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice
D016207:Cytokines; C096000:Ifi1 protein, mouse; D007371:Interferon-gamma; D019204:GTP-Binding Proteins
Irgm1; cytokine induction; fatty acid metabolism; glycolysis; immunity-related GTPase; interferon gamma; macrophage; respiration