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.

Keywords: cancer; microglia; neurodegeneration; neuroinflammation; tissue-resident macrophages.

Figure 1

Ontological origin of macrophage subpopulations in the central nervous system (CNS). A first wave of myeloid cell development takes place in the yolk sac (i) between E7.0 and E8.0 in a process known as primitive hematopoiesis that leads to the generation of erythro-myeloid progenitor (EMP) cells. EMP cells give rise to A1 (cKit⁺Cx3cr1⁻) cells followed by A2 (Cx3cr1⁺) cells that differentiate into microglia, perivascular macrophages (pvMϕ), meningeal macrophages (mMϕ), and choroid plexus macrophages (cpMϕ). Microglia originate exclusively from yolk sac-derived progenitors, while non-parenchymal CNS macrophages are replenished with fetal liver-derived progenitor cells (ii) as part of definitive hematopoiesis. Perinatally, hematopoiesis starts to be restricted to the bone marrow (iii). Among the CNS macrophages, cpMϕ are the only population with substantial constitution from bone marrow progenitors. Microglia, pvMϕ, and mMϕ are considered to be long-living cells that regenerate through self-renewal.

Figure 2

Environmental imprinting of tissue-resident macrophages. Differentiation of precursor cells into specific lineages is determined by binding of lineage-determining transcription factors (LDTFs) and collaborating transcription factors (CTFs) to closely spaced recognition patterns on the DNA. Binding of LDTFs and CTFs selects enhancers as primed or poised. Primed enhancers are marked with characteristic histone modifications such as histone lysine 4 monomethylation (H3K4me1) or dimethylation (H3K4me2). Poised enhancers are defined by the presence of histone H3 lysine 27 trimethylation (H3K27me3). Primed or enhancers show low activity due to the lack of enhancer RNA production or the presence of H3K27me3, that has to be removed to induce an active enhancer state (upper panel). Tissue-resident macrophage populations are exposed to unique environmental cues that lead to genetic and epigenetic imprinting based on signal-dependent transcription factors (SDTF) that bind and activate primed or poised enhancers. Active enhancers are marked by H3K4m1 or H3K4me2 and histone H3 lysine 27 acetylation (H3K27ac) (middle panel). Environmental imprinting induces cell-type-specific functions of different tissue-resident macrophage populations (lower panel).

Figure 3

Microglia and macrophage activation states and effector functions at different stages of disease progression in neurodegenerative disease. (i) Microglia exert protective functions including phagocytosis of cellular debris, uptake of Aβ peptides, and clearance of amyloid plaques at early disease stages. Disease progression leads to changes in microglia functions that limit their ability to confine disease manifestation or even induces inflammatory activation states that cause neuronal and synaptic damage. Induction of Trem2/Apoe signaling was shown to mediate conversion of protective microglia into tissue damaging ones. Recruitment of macrophages from the periphery appears to occur at late disease stages and contributes to disease acceleration due to enhanced inflammation.

Figure 4

Microglia and macrophage activation states and effector functions at different stages of disease progression in brain cancer. (i) Initial stages during neoplastic transformation in primary brain cancers or tumor cell seeding in brain metastasis are detected by microglia. As part of their role in host defense, microglia induce apoptosis in cancer cells. Tumor cells that escape microglia-mediated killing rapidly co-opt them and exploit their function to foster tumor growth. (ii) Brain tumor formation is associated with pronounced recruitment of macrophages from the periphery that starts at early stages and leads to disease acceleration. Transcriptomic analysis identified gene signatures that define tumor-associated microglia (TAM-MG) and macrophages (TAM-BMDM). The respective signatures indicate that TAM-MG rather induce pro-inflammatory responses and exert host defense functions while TAM-BMDMs were associated with wound healing, antigen presentation, and immune suppression.