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

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Details zur Publikation

Autorinnen und Autoren: Ghoochani A, Schwarz M, Yakubov E, Engelhorn T, Dörfler A, Buchfelder M, Bucala R, Savaskan NE, Eyupoglu IY
Zeitschrift: Oncogene
Jahr der Veröffentlichung: 2016
Band: 35
Heftnummer: 48
Seitenbereich: 6246-6261
ISSN: 0950-9232


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.

FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Buchfelder, Michael Prof. Dr.
Lehrstuhl für Neurochirurgie
Dörfler, Arnd Prof. Dr.
Neuroradiologische Abteilung im Radiologischen Institut
Ghoochani, Ali
Neurochirurgische Klinik
Schwarz, Martin
Professur für Experimentelle Augenheilkunde
Yakubov, Eduard
Medizinische Fakultät


Ghoochani, A., Schwarz, M., Yakubov, E., Engelhorn, T., Dörfler, A., Buchfelder, M.,... Eyupoglu, I.Y. (2016). MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis. Oncogene, 35(48), 6246-6261. https://dx.doi.org/10.1038/onc.2016.160

Ghoochani, Ali, et al. "MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis." Oncogene 35.48 (2016): 6246-6261.


Zuletzt aktualisiert 2018-12-11 um 12:08