title: Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization.
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.
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Geming
authors: G
authors: Lu
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Ruihua
authors: R
authors: Zhang
authors: Department of Biological Sciences, Center for Inflammation, Virginia Tech, Blacksburg, Virginia 24061, USA.
authors: Shuo
authors: S
authors: Geng
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Liang
authors: L
authors: Peng
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Padmini
authors: P
authors: Jayaraman
authors: Department of Biological Sciences, Center for Inflammation, Virginia Tech, Blacksburg, Virginia 24061, USA.
authors: Chun
authors: C
authors: Chen
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Feifong
authors: F
authors: Xu
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Jianjun
authors: J
authors: Yang
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Qin
authors: Q
authors: Li
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Hao
authors: H
authors: Zheng
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Kimberly
authors: K
authors: Shen
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Juan
authors: J
authors: Wang
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Xiyu
authors: X
authors: Liu
authors: The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors: Weidong
authors: W
authors: Wang
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Zihan
authors: Z
authors: Zheng
authors: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Chen-Feng
authors: CF
authors: Qi
authors: Institute of Immunology and Molecular Medicine, Jining Medical College, Jining, Shandong 272067, China.
authors: Chuanping
authors: C
authors: Si
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: John Cijiang
authors: JC
authors: He
authors: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors: Kebin
authors: K
authors: Liu
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Sergio A
authors: SA
authors: Lira
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors: Andrew G
authors: AG
authors: Sikora
authors: Department of Biological Sciences, Center for Inflammation, Virginia Tech, Blacksburg, Virginia 24061, USA.
authors: Liwu
authors: http://orcid.org/0000-0001-8870-5299
authors: L
authors: Li
authors: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Institute of Immunology and Molecular Medicine, Jining Medical College, Jining, Shandong 272067, China.
authors: Huabao
authors: H
authors: Xiong
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D050835:Interferon Regulatory Factors / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010641:Phenotype; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D012772:Shock, Septic / Q000276:immunology*
chemical_list: D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; C090663:N(6)-(1-iminoethyl)lysine; D020030:Nitric Oxide Donors; D026423:S-Nitroso-N-Acetylpenicillamine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D008239:Lysine