Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization

Geming Lu, Ruihua Zhang, Shuo Geng, Liang Peng, Padmini Jayaraman, Chun Chen, Feifong Xu, Jianjun Yang, Qin Li, Hao Zheng, Kimberly Shen, Juan Wang, Xiyu Liu, Weidong Wang, Zihan Zheng, Chen-Feng Qi, Chuanping Si, John Cijiang He, Kebin Liu, Sergio A. Lira, Andrew G. Sikora, Liwu Li () and Huabao Xiong ()
Additional contact information
Geming Lu: Immunology Institute, Icahn School of Medicine at Mount Sinai
Ruihua Zhang: Immunology Institute, Icahn School of Medicine at Mount Sinai
Shuo Geng: Center for Inflammation, Virginia Tech
Liang Peng: Immunology Institute, Icahn School of Medicine at Mount Sinai
Padmini Jayaraman: Immunology Institute, Icahn School of Medicine at Mount Sinai
Chun Chen: Center for Inflammation, Virginia Tech
Feifong Xu: Immunology Institute, Icahn School of Medicine at Mount Sinai
Jianjun Yang: Immunology Institute, Icahn School of Medicine at Mount Sinai
Qin Li: Immunology Institute, Icahn School of Medicine at Mount Sinai
Hao Zheng: Immunology Institute, Icahn School of Medicine at Mount Sinai
Kimberly Shen: Immunology Institute, Icahn School of Medicine at Mount Sinai
Juan Wang: Immunology Institute, Icahn School of Medicine at Mount Sinai
Xiyu Liu: Immunology Institute, Icahn School of Medicine at Mount Sinai
Weidong Wang: The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Medical College of Cornell University
Zihan Zheng: Immunology Institute, Icahn School of Medicine at Mount Sinai
Chen-Feng Qi: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Chuanping Si: Institute of Immunology and Molecular Medicine, Jining Medical College
John Cijiang He: Immunology Institute, Icahn School of Medicine at Mount Sinai
Kebin Liu: Medical College of Georgia, Georgia Regents University
Sergio A. Lira: Immunology Institute, Icahn School of Medicine at Mount Sinai
Andrew G. Sikora: Immunology Institute, Icahn School of Medicine at Mount Sinai
Liwu Li: Center for Inflammation, Virginia Tech
Huabao Xiong: Immunology Institute, Icahn School of Medicine at Mount Sinai

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract Here we show that iNOS-deficient mice display enhanced classically activated M1 macrophage polarization without major effects on alternatively activated M2 macrophages. eNOS and nNOS mutant mice show comparable M1 macrophage polarization compared with wild-type control mice. Addition of N6-(1-iminoethyl)-L-lysine dihydrochloride, an iNOS inhibitor, significantly enhances M1 macrophage polarization while S-nitroso-N-acetylpenicillamine, a NO donor, suppresses M1 macrophage polarization. NO derived from iNOS mediates nitration of tyrosine residues in IRF5 protein, leading to the suppression of IRF5-targeted M1 macrophage signature gene activation. Computational analyses corroborate a circuit that fine-tunes the expression of IL-12 by iNOS in macrophages, potentially enabling versatile responses based on changing microenvironments. Finally, studies of an experimental model of endotoxin shock show that iNOS deficiency results in more severe inflammation with an enhanced M1 macrophage activation phenotype. These results suggest that NO derived from iNOS in activated macrophages suppresses M1 macrophage polarization.

Date: 2015
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DOI: 10.1038/ncomms7676

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