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. LiraAndrew G. Sikora, Liwu Li, Huabao Xiong

Research output: Contribution to journalArticle

72 Scopus citations

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.

Original languageEnglish (US)
Article number6676
JournalNature communications
Volume6
DOIs
StatePublished - Mar 30 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Lu, G., Zhang, R., Geng, S., Peng, L., Jayaraman, P., Chen, C., Xu, F., Yang, J., Li, Q., Zheng, H., Shen, K., Wang, J., Liu, X., Wang, W., Zheng, Z., Qi, C. F., Si, C., He, J. C., Liu, K., ... Xiong, H. (2015). Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. Nature communications, 6, [6676]. https://doi.org/10.1038/ncomms7676