Abstract
Polarization of macrophages to M1 or M2 cells is important for mounting responses against bacterial and helminth infections, respectively. Jumonji domain containing-3 (Jmjd3), a histone 3 Lys27 (H3K27) demethylase, has been implicated in the activation of macrophages. Here we show that Jmjd3 is essential for M2 macrophage polarization in response to helminth infection and chitin, though Jmjd3 is dispensable for M1 responses. Furthermore, Jmjd3 (also known as Kdm6b) is essential for proper bone marrow macrophage differentiation, and this function depends on demethylase activity of Jmjd3. Jmjd3 deficiency affected trimethylation of H3K27 in only a limited number of genes. Among them, we identified Irf4 as encoding a key transcription factor that controls M2 macrophage polarization. Collectively, these results show that Jmjd3-mediated H3K27 demethylation is crucial for regulating M2 macrophage development leading to anti-helminth host responses.
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Acknowledgements
We thank all the colleagues in our laboratory, E. Kamada for secretarial assistance and Y. Fujiwara, M. Kumagai, R. Abe, N. Kitagaki and S. Yumikura for technical assistance. This work was supported by the Special Coordination Funds of the Japanese Ministry of Education, Culture, Sports, Science and Technology, and grants from the Ministry of Health, Labour and Welfare in Japan, the Global Center of Excellence Programs of Osaka University and Nagasaki University and the US National Institutes of Health (P01 AI070167). Computational time was provided by the Super Computer System at the Human Genome Center, Institute of Medical Science, The University of Tokyo. A.V. was partly supported by a Japanese government scholarship.
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T. Satoh and O.T. designed and performed experiments. Y.K., T. Miyake, K.M., T.O. and T. Saitoh performed experiments. A.V., Y.T., D.M.S. and K. Nakai analyzed ChIP-Seq data. K. Yasuda and K. Nakanishi performed N. brasiliensis infection experiments. K.H., T. Matsuyama and K. Yui provided Irf4−/− mice. T.T. performed histological examination. O.T., T. Satoh and S.A. wrote the manuscript. S.A. supervised the project. A.V. and K.Y. contributed equally to this work.
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Supplementary Text and Figures
Supplementary Figures 1–10 and Supplementary Methods (PDF 637 kb)
Supplementary Table 1
Gene expression profiles in WT and Jmjd3−/− M-BMM with and without LPS stimulation. (XLS 1329 kb)
Supplementary Table 2
Gene expression profiles in WT and Jmjd3−/− M-BMM with and without LPS stimulation. (XLS 1965 kb)
Supplementary Table 3
Gene H3K27 methylation status and expression in WT and Jmjd3−/− M-BMM. (XLS 2344 kb)
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Satoh, T., Takeuchi, O., Vandenbon, A. et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 11, 936–944 (2010). https://doi.org/10.1038/ni.1920
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DOI: https://doi.org/10.1038/ni.1920
