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MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis

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Abstract

Microglial cells in the brain tumor microenvironment are associated with enhanced glioma malignancy. They persist in an immunosuppressive M2 state at the peritumoral site and promote the growth of gliomas. Here, we investigated the underlying factors contributing to the abolished immune surveillance. We show that brain tumors escape pro-inflammatory M1 conversion of microglia via CD74 activation through the secretion of the cytokine macrophage migration inhibitory factor (MIF), which results in a M2 shift of microglial cells. Interruption of this glioma–microglial interaction through an antibody-neutralizing approach or small interfering RNA (siRNA)-mediated inhibition prolongs survival time in glioma-implanted mice by reinstating the microglial pro-inflammatory M1 function. We show that MIF-CD74 signaling inhibits interferon (IFN)-γ secretion in microglia through phosphorylation of microglial ERK1/2 (extracellular signal-regulated protein kinases 1 and 2). The inhibition of MIF signaling or its receptor CD74 promotes IFN-γ release and amplifies tumor death either through pharmacological inhibition or through siRNA-mediated knockdown. The reinstated IFN-γ secretion leads both to direct inhibition of glioma growth as well as inducing a M2 to M1 shift in glioma-associated microglia. Our data reveal that interference with the MIF signaling pathway represents a viable therapeutic option for the restoration of IFN-γ-driven immune surveillance.

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Acknowledgements

Our work is supported by the German Research Foundation (DFG Ey 94/2-1).

Author contributions

NES and IYE conceived and designed the study. AG and MAS performed all experiments. MAS and TE contributed to the in vivo experiments and MR imaging analysis under the supervision of AD, MAS, AG, TE, RB and MB analyzed and interpreted the data and discussed the data with all authors. NES and IYE wrote the manuscript. All authors contributed to the preparation of the final manuscript. AG performed the present work in fulfillment of the requirements for obtaining the degree Dr rer. biol. hum. at the Friedrich Alexander University of Erlangen-Nürnberg (FAU).

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Correspondence to I Y Eyüpoglu.

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Ghoochani, A., Schwarz, M., Yakubov, E. et al. MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis. Oncogene 35, 6246–6261 (2016). https://doi.org/10.1038/onc.2016.160

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