Brain-Resident Microglia and Blood-Borne Macrophages Orchestrate Central Nervous System Inflammation in Neurodegenerative Disorders and Brain Cancer

Abstract

Inflammation is a hallmark of different central nervous system (CNS) pathologies. It has been linked to neurodegenerative disorders as well as primary and metastatic brain tumors. Microglia, the brain-resident immune cells, are emerging as a central player in regulating key pathways in CNS inflammation. Recent insights into neuroinflammation indicate that blood-borne immune cells represent an additional critical cellular component in mediating CNS inflammation. The lack of experimental systems that allow for discrimination between brain-resident and recruited myeloid cells has previously halted functional analysis of microglia and their blood-borne counterparts in brain malignancies. However, recent conceptual and technological advances, such as the generation of lineage tracing models and the identification of cell type-specific markers provide unprecedented opportunities to study the cellular functions of microglia and macrophages by functional interference. The use of different “omic” strategies as well as imaging techniques has significantly increased our knowledge of disease-associated gene signatures and effector functions under pathological conditions. In this review, recent developments in evaluating functions of brain-resident and recruited myeloid cells in neurodegenerative disorders and brain cancers will be discussed and unique or shared cellular traits of microglia and macrophages in different CNS disorders will be highlighted. Insight from these studies will shape our understanding of disease- and cell-type-specific effector functions of microglia or macrophages and will open new avenues for therapeutic intervention that target aberrant functions of myeloid cells in CNS pathologies.

Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas

“…However, the majority of immune cells in gliomas are not TILs but rather glioma‐associated microglia and macrophages (GAMs, referring explicitly to microglia and macrophages in the glioma microenvironment in distinction to microglia and macrophages (M/M) without a relation to any tumor microenvironment) . The origin of GAMs was investigated in several different GBM mouse models showing discrepant findings regarding the amount of recruited macrophages and microglia that contribute to the total GAM population . GAMs infiltrate the tumor center via chemoattraction , potentially playing a role in TIL recruitment.…”

“…Nevertheless, the functions and the ability to initiate an effective antitumor immune response as well as the prognostic impact onto patients’ clinical course of tumor‐associated macrophages (TAMs) still remain unclear and are ambivalently discussed (eg, positive vs. negative prognostic effects). This has recently been reviewed in detail with regard to GAMs . External stimuli like interferon‐γ (IFN‐γ), tumor necrosis factor (TNFα) or the interleukins IL‐4 and IL‐10 considerably influence macrophages in general and tumor‐associated macrophages (TAMs, referring to macrophages in non‐CNS cancer entities) eg, .…”

“…However, the M1/M2 model is strongly debated in general and evidence for its suitability for neoplasms of the central nervous system (CNS) is still poor . Despite potentially distinct immunological properties of macrophages and microglia, it is still difficult to differentiate the exact origin of GAMs .…”

Favorable and unfavorable roles of microglia and macrophages in the pathologic central nervous system

“…Microglia and blood-borne macrophages play major roles in the pathophysiological processes in various kinds of pathologies of the central nervous system (CNS) by releasing numerous bioactive substances, including cytokines, growth factors, and reactive oxygen/nitrogen species, and phagocytosing degenerating cells and materials [1][2][3][4] . In this article, we use "microglia" to denote resident microglia in the CNS, and "macrophages" to denote cells derived from circulating monocytes that have invaded (typically inflamed) CNS lesions with a disrupted blood-brain barrier (BBB).…”

“…More recently, it is well-known that both cell types play major roles in pathophysiological processes [2,11,12] . The neuroinflammatory processes influence outcomes of CNS diseases or injuries in both favorable and unfavorable ways.…”