Journal Article

Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis

Loudon, Kevin W., Kaser, Arthur, Kaplan, Mariana J., Tuong, Zewen K., Murphy, Michael P., Bashant, Kathleen R., Lok, Laurence S. C., Clatworthy, Menna R., Jing, Chenzhi, Castro-Dopico, Tomas, Richoz, Nathan, Cader, Zaeem, Fitzpatrick, Susan, Banham, Gemma D., Mathews, Rebeccah J., Ferdinand, John R., Siegel, Richard M., Johnson, Randall S.

2020

Overview

IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.

• Publisher: National Academy of Sciences
• Subject: Animal models / Animals / Antibodies / Arthritis / Autoantibodies / Autoimmune diseases / Biological Sciences / Cell activation / Cells, Cultured / Cellular Reprogramming - physiology / Chronic conditions / Crosslinking / Depletion / Dinoprostone - genetics / Dinoprostone - metabolism / Energy Metabolism / Gene Expression Regulation / Glycolysis / Glycolysis - physiology / Humans / Hypoxia / Hypoxia-inducible factor 1a / IL-1β / Immunoglobulin G / Immunoglobulin G - metabolism / Immunology and Inflammation / Inflammation / Interleukin-1beta - genetics / Interleukin-1beta - metabolism / Kidney - cytology / Kidneys / Lupus / Lupus nephritis / Lupus Nephritis - metabolism / Macrophages / Metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Molecular modelling / Nephritis / Reactive Oxygen Species / Receptors, IgG - genetics / Receptors, IgG - metabolism / Rheumatoid arthritis / Systemic lupus erythematosus / Therapeutic applications / TOR protein