MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis
MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis
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DOI：
10.1038/onc.2016.160
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发表时间：
2016-12-01
期刊：
影响因子：
8
通讯作者：
Eyupoglu, I. Y.
中科院分区：
文献类型：
--
作者：
Ghoochani, A.;Schwarz, M. A.;Eyupoglu, I. Y.
脑肿瘤微环境中的小胶质细胞与增强的胶质瘤恶性程度有关。它们在瘤周部位持续处于免疫抑制的M2状态，并促进胶质瘤的生长。在这里，我们调查了导致废除免疫监测的潜在因素。我们发现，脑肿瘤通过分泌细胞因子巨噬细胞移动抑制因子(MIF)，通过CD74激活逃避小胶质细胞的促炎性M1转化，导致小胶质细胞M2移位。通过抗体中和方法或小干扰RNA(SiRNA)介导的抑制来阻断这种胶质瘤-小胶质细胞的相互作用，可以通过恢复小胶质细胞促炎M1功能来延长胶质瘤移植小鼠的存活时间。我们发现MIF-CD74信号通过小胶质细胞ERK1/2(细胞外信号调节蛋白激酶1和2)的磷酸化来抑制小胶质细胞的干扰素-γ的分泌。MIF信号或其受体CD74的抑制通过药物抑制或siRNA介导的基因敲除促进了干扰素-γ的释放，放大了肿瘤的死亡。恢复干扰素-γ的分泌既直接抑制了胶质瘤的生长，又诱导了与胶质瘤相关的小胶质细胞M2向M1的转变。我们的数据显示，干扰MIF信号通路是恢复干扰素-γ驱动的免疫监视的一个可行的治疗选择。
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 proinflammatory M1 function. We show that MIF-CD74 signaling inhibits interferon (IFN)-gamma 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-gamma release and amplifies tumor death either through pharmacological inhibition or through siRNAmediated knockdown. The reinstated IFN-gamma 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-gamma-driven immune surveillance.