Microglia are resident macrophages of the central nervous system and significantly contribute to overall brain function by participating in phagocytosis during development, homeostasis, and diseased states. Phagocytosis is a highly complex process that is specialized for the uptake and removal of opsonized and non-opsonized targets, such as pathogens, apoptotic cells, and cellular debris. While the role of phagocytosis in mediating classical innate and adaptive immune responses has been known for decades, it is now appreciated that phagocytosis is also critical throughout early neural development, homeostasis, and initiating repair mechanisms. As such, modulating phagocytic processes has provided unexplored avenues with the intent of developing novel therapeutics that promote repair and regeneration in the CNS. Here, we review the functional consequences that phagocytosis plays in both the healthy and diseased CNS, and summarize how phagocytosis contributes to overall pathophysiological mechanisms involved in brain injury and repair.

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SummaryDysfunction of microglia, the brain’s immune cells, is linked to neurodegeneration. Homozygous missense mutations in TREM2 cause Nasu-Hakola disease (NHD), an early-onset dementia. To study the consequences of these TREM2 variants, we generated induced pluripotent stem cell-derived microglia-like cells (iPSC-MGLCs) from patients with NHD caused by homozygous T66M or W50C missense mutations. iPSC-MGLCs expressed microglial markers and secreted higher levels of TREM2 than primary macrophages. TREM2 expression and secretion were reduced in variant lines. LPS-mediated cytokine secretion was comparable between control and TREM2 variant iPSC-MGLCs, whereas survival was markedly reduced in cells harboring missense mutations when compared with controls. Furthermore, TREM2 missense mutations caused a marked impairment in the phagocytosis of apoptotic bodies, but not in Escherichia coli or zymosan substrates. Coupled with changes in apoptotic cell-induced cytokine release and migration, these data identify specific deficits in the ability of iPSC-MGLCs harboring TREM2 missense mutations to respond to specific pathogenic signals.

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Chalcones are plant metabolites with potential for therapeutic exploitation as antioxidant, anti-inflammatory, and antiproliferative agents. Here we explored the neuroprotective effects of 2,2′,5′-trihydroxychalcone (225THC), a potent antioxidant with radical-scavenging properties. 225THC was found to be a potent inhibitor of apoptosis in stimulated primary rat neuronal cultures. This was likely mediated by an anti-inflammatory effect on microglial cells since 225THC inhibited LPS-stimulated TNF-α and IL-6 secretion from primary rat microglia and modulated the cytokine/chemokine profile of BV2 microglial cells. Additionally, 225THC inhibited LPS-evoked inducible nitric oxide synthase expression but did not influence endogenous superoxide generation. Microglial flow cytometric analyses indicated the 225THC treatment induced a shift from an M1-like phenotype to a more downregulated microglial profile. Taken together these data suggest that the chalcone 2,2′,5′-trihydroxychalcone can modulate neuroinflammatory activation in brain-derived microglia and holds promise as a therapeutic in neuroinflammatory conditions.

XBD173 and etifoxine are translocator protein (TSPO) ligands that modulate inflammatory responses in preclinical models. Limited human pharmacokinetic data is available for either molecule, and the binding affinity of etifoxine for human TSPO is unknown. To allow for design of human challenge experiments, we derived pharmacokinetic data for orally administered etifoxine (50 mg 3 times daily) and XBD173 (90 mg once daily) and determined the binding affinity of etifoxine for TSPO. For XBD173, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 1.0 nM, which is similar to XBD173 binding affinity. For etifoxine, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 0.31 nM, substantially lower than the Ki for etifoxine in human brain derived here (7.8 μM, 95% CI 4.5–14.6 μM). We conclude that oral XBD173 dosing at 90 mg once daily will achieve pharmacologically relevant TSPO occupancy. However, the occupancy is too low for TSPO mediated effects after oral dosing of etifoxine at 50 mg 3 times daily.

Background: Neuroinflammation is associated with neurodegenerative disease. PET radioligands targeting the 18 kDa translocator protein (TSPO) has been used as in vivo markers of neuroinflammation, but there is an urgent need for novel probes with an improved signal-to-noise ratio. Flutriciclamide ( 18 F-GE180) is a recently developed third generation TSPO ligand. In this first study, we evaluated the optimum scan duration and kinetic modeling strategies for 18 F-GE180 PET in (older) healthy controls. Methods: Ten healthy controls, six TSPO high affinity binders (HABs) and four mixed affinity binders (MABs), were recruited. All subjects had detailed neuropsychological tests and MRI, followed by a 210 min 18 F-GE180 dynamic PET/CT scan using a metabolite corrected arterial plasma input function. Five different kinetic models describing brain 18 F-GE180 uptake were interrogated: irreversible and reversible two-tissue compartment models, a reversible one-tissue model and two models with an extra irreversible vascular compartment. The optimum scan length was investigated based on 210 min scan data. The feasibility of generating parametric maps was also investigated using graphical analysis. Results: 18 F-GE180 concentration was higher in plasma than in whole blood during the entire scan duration. Using the kinetic models, the volume of distribution (V T ) was 0.17 in HABs and 0.12 in MABs. The model that best represented brain 18 F-GE180 kinetics across regions was the reversible two-tissue model and 90 min was determined as the optimum scan length required to obtain stable estimates. Logan graphical analysis with arterial input function gave a V T highly consistent with 2TCM4k, which could be used for voxel-wise analysis. Conclusions: We report here for the first time the kinetic properties of the novel 3 nd generation TSPO PET ligand, 18 F-GE180, in humans: 2TCM4k is the optimal method to quantify the brain uptake and 90 min is the optimal scan length, and Logan approach could be used to generate parametric maps. While these control subjects have shown relatively low V T , the methodology presented in this study forms the basis for quantification of future PET studies using 18 F-GE180 in different pathologies.Background: Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene increase the risk of developing Alz-heimer's disease (AD). In the brain, TREM2 is highly expressed by microglia. TREM2 appears to mediate microglial phagocytosis and the expression of an anti-inflammatory phenotype. Loss of this function may contribute to the pathogenesis of AD and shift cell behaviour towards a more harmful pro-inflammatory phenotype. An important goal is to establish whether AD patients with/without a TREM2 risk variant share a similar microglial response to pathology. Methods:Human brain sections containing the hippocampal regions CA1 and CA4 were obtained from comparable AD cases with (AD/TREM2+) and without (AD/TREM2-) TREM2 variants, and Control/healthy cases without TREM2 variants (Control/TREM2-). ...

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