Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors

Abstract

Myeloid cells are an essential part of the glioblastoma microenvironment. However, in brain tumors the function of these immune cells is not sufficiently clarified. In our study, we investigated differential pro-angiogenic activities of resident microglia and peripheral macrophages and their impact on glioma vascularization and progression. Our data demonstrate stable accumulation of microglia/macrophages during tumor growth. These cells often interact with tumor blood vessels correlating with vascular remodeling. Here, we identified resident microglia as well as peripheral macrophages as part of the perivascular niche, primarily contacting endothelial cells. We found overexpression of a variety of pro-angiogenic molecules within freshly isolated microglia/macrophages from glioma. CXCL2, until now a poorly described chemokine, was strongly up-regulated and showed better angiogenic activity than VEGF in vitro. Blocking the CXCL2-CXCR2 signaling pathway resulted in considerably diminished glioma sizes. Additionally, the importance of microglia/macrophages in tumor angiogenesis was confirmed by depletion of these cells in vivo. Vessel density decreased by 50% leading to significantly smaller tumor volumes. Remarkably, selective reduction of resident microglia affected tumoral vessel count comparable to ablation of the whole myeloid cell fraction. These results provide evidence that resident microglia are the crucial modulatory cell population playing a central role in regulation of vascular homeostasis and angiogenesis in brain tumors. Thus, resident microglia represent an alternative source of pro-angiogenic growth factors and cytokines.

Role of neuroinflammation in ischemic stroke

“…[37] Microglia is considered as the resident macrophage in the brain and the initial responders to tissue damage. [58] Microglia express receptors that respond to various stimuli that may as a consequence result in there activation. [59] A large number of studies indicate that microglia expresses different proteins and cytokines that display different role to express different function.…”

The impact of high and low dose ionising radiation on the central nervous system

“…The pro-inflammatory state of activated microglia, or the M1 type classical activation state, can be cytotoxic to surrounding cells, and when unregulated can propagate tissue damage and cause secondary injury [32], [33]. Correspondingly, neuroinflammation is thought to be implicated in multifarious functions and pathological states in the CNS, including the modulation of neurogenesis and neuronal development [25], [34], [35], synaptic stripping and neuronal dysfunction [36], [37], and is now widely implicated in the pathogenesis and progression of many neurodegenerative disorders [38], [39], [40], [41], [42], [43], [44], [45]. Alternatively, an M2 microglial activation state is not neurotoxic, transiently conferring neuroprotection and anti-inflammatory properties in response to injury [46].…”

Perivascular niches as points of the utmost expression of tumor microenvironment

“…In response to angiogenic signals, pericytes initially dissociate and lose the capacity of suppressing endothelial proliferation. On the other hand, pericytes derive from precursors, such as mesenchymal stem cells (MSCs) or hematopoietic precursors, induced to differentiate by the tumor microenvironment [40] and by transforming growth factor-β (TGF-β) [10]. Their recruitment depends on matrix metalloprotease (MMP-9) produced by CD45+ cells via SDF-1/CXCR4 signaling [41,42] and VEGF released from the extracellular matrix.…”

“…Their recruitment depends on matrix metalloprotease (MMP-9) produced by CD45+ cells via SDF-1/CXCR4 signaling [41,42] and VEGF released from the extracellular matrix. It has been demonstrated that in mice with NG2 deficiency, as well as with collagen VI deficiency [43], the tumor growth is reduced, and that GSCs give rise to pericytes to support tumor growth and vessel function through remodeling PVN [10].…”

“…PVN occur besides perinecrotic and invasive niches [8], but they should be further substantiated and specified because of the glioblastoma (GB) heterogeneity and the various forms of neo-vascularization [9]. An important role is played by glioma-associated microglia/macrophages (GAMs), chemokine signaling and pericytes [10,11].…”