Nature Immunol. 11: 936-944 (2010)

Macrophages are functionally polarized into M1 and M2 cells in response to infection with microorganisms and host mediators. Whereas M1 macrophages are important for host responses against bacterial infection, M2 Macrophages, also known as alternatively activated macrophages, play an important role in responses to parasite infection, tissue remodeling, angiogenesis and tumor progression. However, molecular mechanisms regulating M1 and M2 polarization has yet to be identified. Jmjd3, a histone H3 Lys27 me3 demethylase, has been implicated in the activation of macrophages. In the present study, we identified Jmjd3 as the Toll-like receptor-inducible gene, and show that Jmjd3 is essential for M2 macrophage polarization to helminth infection and chitin. In contrast, Jmjd3 is dispensable for M1 responses. Furthermore, Jmjd3 is critical for proper bone marrow macrophage differentiation in a demethylase activity dependent manner. Chromatin immunoprecipitation on sequencing (ChIP-seq) analysis revealed that Jmjd3 deficiency affected trimethylation of H3K27 on only a limited numbers of genes. Among them, we identified Irf4 as the target transcription factor critical for controlling M2 macrophage polarization. Collectively, these results show that JMJD3-mediated H3K27me3 demethylation is critical for regulating M2 macrophage development leading to anti-helminth host responses.