title: MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis.
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.
authors.affiliation: Department of Neurosurgery, Universitätsklinikum Erlangen, Medical Faculty of the Friedrich Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ghoochani
authors.affiliation: Department of Neurosurgery, Universitätsklinikum Erlangen, Medical Faculty of the Friedrich Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: Schwarz
authors.affiliation: Department of Neurosurgery, Universitätsklinikum Erlangen, Medical Faculty of the Friedrich Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Yakubov
authors.affiliation: Department of Neuroradiology, Universitätsklinikum Erlangen, Medical Faculty of the Friedrich Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Engelhorn
authors.affiliation: Department of Neuroradiology, Universitätsklinikum Erlangen, Medical Faculty of the Friedrich Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Doerfler
authors.affiliation: Department of Neurosurgery, Universitätsklinikum Erlangen, Medical Faculty of the Friedrich Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Buchfelder
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bucala
authors.affiliation: Department of Neurosurgery, Universitätsklinikum Erlangen, Medical Faculty of the Friedrich Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.|BiMECON Ent., Kurfürstenstrasse 21, Berlin, Germany.
authors.forename: N E
authors.initials: NE
authors.lastname: Savaskan
authors.affiliation: Department of Neurosurgery, Universitätsklinikum Erlangen, Medical Faculty of the Friedrich Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: I Y
authors.initials: IY
authors.lastname: Eyüpoglu
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D008954:Models, Biological; D010587:Phagocytosis; D051381:Rats; D015398:Signal Transduction
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; C045084:invariant chain; D007371:Interferon-gamma