Journal Article

Reprogramming of macrophages employing gene regulatory and metabolic network models

Oswald, Marcus, Röll, Daniela, Osen, Wolfram, König, Rainer, Kolte, Amol, Eichmüller, Stefan B., Hörhold, Franziska, Eisel, David

2020

Overview

Upon exposure to different stimuli, resting macrophages undergo classical or alternative polarization into distinct phenotypes that can cause fatal dysfunction in a large range of diseases, such as systemic infection leading to sepsis or the generation of an immunosuppressive tumor microenvironment. Investigating gene regulatory and metabolic networks, we observed two metabolic switches during polarization. Most prominently, anaerobic glycolysis was utilized by M1-polarized macrophages, while the biosynthesis of inosine monophosphate was upregulated in M2-polarized macrophages. Moreover, we observed a switch in the urea cycle. Gene regulatory network models revealed E2F1, MYC, PPARγ and STAT6 to be the major players in the distinct signatures of these polarization events. Employing functional assays targeting these regulators, we observed the repolarization of M2-like cells into M1-like cells, as evidenced by their specific gene expression signatures and cytokine secretion profiles. The predicted regulators are essential to maintaining the M2-like phenotype and function and thus represent potential targets for the therapeutic reprogramming of immunosuppressive M2-like macrophages.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Anaerobiosis / Animals / Apoptosis / Biology and Life Sciences / Biosynthesis / Cancer / Cell cycle / Cytokines / Cytokines - metabolism / Diseases / Disseminated infection / Gene expression / Gene Expression Profiling / Gene Expression Regulation / Gene Regulatory Networks / Genes / Genotype & phenotype / Glycolysis / Health aspects / Immunosuppression Therapy / Immunosuppressive Agents - therapeutic use / Infection / Infections / Inflammation / Inosine monophosphate / Inosine Monophosphate - metabolism / Lymphocytes / Macrophage Activation / Macrophages / Macrophages - metabolism / Medical research / Medicine and Health Sciences / Metabolic networks / Metabolism / Metabolites / Mice / Mice, Inbred C57BL / Myc protein / Nitric oxide / Pathogens / Periodical publishing / Phenotype / Phenotypes / Physiological aspects / Polarization / Regulators / Sepsis / Signatures / Software / Stat6 protein / Switches / Switching theory / Tumor Microenvironment / Tumors / Urea