Characteristics of the Alternative Phenotype of Microglia/Macrophages and its Modulation in Experimental Gliomas

Abstract

Microglia (brain resident macrophages) accumulate in malignant gliomas and instead of initiating the anti-tumor response, they switch to a pro-invasive phenotype, support tumor growth, invasion, angiogenesis and immunosuppression by release of cytokines/chemokines and extracellular matrix proteases. Using immunofluorescence and flow cytometry, we demonstrate an early accumulation of activated microglia followed by accumulation of macrophages in experimental murine EGFP-GL261 gliomas. Those cells acquire the alternative phenotype, as evidenced by evaluation of the production of ten pro/anti-inflammatory cytokines and expression profiling of 28 genes in magnetically-sorted CD11b+ cells from tumor tissues. Furthermore, we show that infiltration of implanted gliomas by amoeboid, Iba1-positive cells can be reduced by a systematically injected cyclosporine A (CsA) two or eight days after cell inoculation. The up-regulated levels of IL-10 and GM-CSF, increased expression of genes characteristic for the alternative and pro-invasive phenotype (arg-1, mt1-mmp, cxcl14) in glioma-derived CD11b+ cells as well as enhanced angiogenesis and tumor growth were reduced in CsA-treated mice. Our findings define for the first time kinetics and biochemical characteristics of glioma-infiltrating microglia/macrophages. Inhibition of the alternative activation of tumor-infiltrating macrophages significantly reduced tumor growth. Thus, blockade of microglia/macrophage infiltration and their pro-invasive functions could be a novel therapeutic strategy in malignant gliomas.

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

“…5B). All four chemokines promote M2 protumor polarization of macrophages (23)(24)(25)(26). Thus, our gene-expression analysis suggests that loss of Ptprd in the tumor cells might lead to the activation of genetic programs that affect the immune response, and in particular macrophages.…”

“…To determine whether macrophages were present in the tumors from our mice, we stained Ptprd +/+ p16 −/− , Ptprd +/− p16 −/− , and Ptprd −/− p16 −/− tumors with the Iba1 macrophage marker. Although the quantity of Iba1 + cells was similar for all tumors, we noted that tumors from Ptprd +/− p16 −/− tended to have amoeboid macrophage morphology, which is associated with a protumorigenic phenotype (25,31,32) (Fig. 5C); this was concentrated in the larger tumors.…”

“…Our gene-expression analysis of the tumor cells demonstrated that activation of genetic programs governing immune response and macrophage response were at play. More specifically, Ptprd +/− p16 −/− tumors had activated genes involved in up-regulation of several chemokines, all of which promote M2 polarization (23)(24)(25)(26). Macrophages can enhance tumor cell survival by promoting tumor growth, invasion, or immunosuppression (27)(28)(29)(38)(39)(40).…”

Glioblastoma cells induce differential glutamatergic gene expressions in human tumor-associated microglia/macrophages and monocyte-derived macrophages

“…8 For example, analysis of TAMs in a murine glioma model has reported the acquisition of the alternative, pro-tumor phenotype of TAMs in the course of tumor development. 11 Moreover, a study has shown that a 48-hour incubation with glioma cells triggered an alternative, tumor-promoting profile in human monocytes. 16 Therefore, we studied the alternative, tumor-promoting profile of fTAMs and compared this with cultured TAMs and MDMs after 48-hour indirect co-culture with NCH82 by examining the gene expressions of interleukin (IL)-10, vascular endothelial growth factor (VEGF) and mannose receptor (MRC1), 3 key immunosuppressive molecules expressed in TAMs.…”

“…9,10 TAMs in the presence of glioma cells become immunosuppressive and elicit an anti-inflammatory response by increasing the expression and release of cytokines such as IL-10 and VEGF, thereby contributing to a milieu that promotes the survival and growth of the glioblastoma cells. 8,11,12 Microglia express functional glutamate receptors, 13,14 and microglia as well as macrophages are capable of inducing expression of glutamate transporters and glutamine synthetase in neuropathological conditions, 15 suggesting a functional role of microglia and macrophages in glutamate signaling. However, little is known about the role of TAMs in response to the dysregulation of glutamate signaling in a glioblastoma microenvironment.…”