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

Ghoochani A, Schwarz M, Yakubov E, Engelhorn T, Dörfler A, Buchfelder M, Bucala R, Savaskan NE, Eyupoglu IY (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Oncogene Springer Nature

Book Volume: 35

Pages Range: 6246-6261

Journal Issue: 48

DOI: 10.1038/onc.2016.160

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 with CRIS profile

Ali Ghoochani Department of Neurosurgery Martin Schwarz Professur für Experimentelle Augenheilkunde Eduard Yakubov Medizinische Fakultät Tobias Martin Engelhorn Department of Neuroradiology Arnd Dörfler Department of Neuroradiology Michael Buchfelder Lehrstuhl für Neurochirurgie

Involved external institutions

Yale University US United States (USA) (US)

How to cite

APA:

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

MLA:

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

BibTeX: Download