Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production.
Inflammatory maturation of M1 macrophages by proinflammatory stimuli such as toll like receptor ligands results in profound metabolic reprogramming resulting in commitment to aerobic glycolysis as evidenced by repression of mitochondrial oxidative phosphorylation (OXPHOS) and enhanced glucose utilization. In contrast, "alternatively activated" macrophages adopt a metabolic program dominated by fatty acid-fueled OXPHOS. Despite the known importance of these developmental stages on the qualitative aspects of an inflammatory response, relatively little is know regarding the regulation of these metabolic adjustments. Here we provide evidence that the immunosuppressive cytokine IL-10 defines a metabolic regulatory loop. Our data show for the first time that lipopolysaccharide (LPS)-induced glycolytic flux controls IL-10-production via regulation of mammalian target of rapamycin (mTOR) and that autocrine IL-10 in turn regulates macrophage nitric oxide (NO) production. Genetic and pharmacological manipulation of IL-10 and nitric oxide (NO) establish that metabolically regulated autocrine IL-10 controls glycolytic commitment by limiting NO-mediated suppression of OXPHOS. Together these data support a model where autocine IL-10 production is controlled by glycolytic flux in turn regulating glycolytic commitment by preserving OXPHOS via suppression of NO. We propose that this IL-10-driven metabolic rheostat maintains metabolic equilibrium during M1 macrophage differentiation and that perturbation of this regulatory loop, either directly by exogenous cellular sources of IL-10 or indirectly via limitations in glucose availability, skews the cellular metabolic program altering the balance between inflammatory and immunosuppressive phenotypes.
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States.
Walter A
WA
Baseler
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States; Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
Luke C
LC
Davies
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States.
Laura
L
Quigley
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States.
Lisa A
LA
Ridnour
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States.
Jonathan M
JM
Weiss
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, United States.
S Perwez
SP
Hussain
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States.
David A
DA
Wink
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States. Electronic address: mcvicard@mail.nih.gov.
Daniel W
DW
McVicar
D000818:Animals; D019898:Autocrine Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
C508609:IL10 protein, human; D008070:Lipopolysaccharides; D016753:Interleukin-10; D009569:Nitric Oxide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
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