Intracortical injection of immune checkpoint inhibitor promotes monocyte/macrophage infiltration and restores microglial function and neuronal activity in an AD mouse model
Taeyoung ParkLeechung ChangSeung Won ChungSeowoo LeeSungjun BaeCarlo CondelloYong Ho KimJaecheol LeeHan-Joo KimHo-Keun KwonMinah Suh
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Understanding the intricate interplay among immune responses and homeostatic cell function in Alzheimer's disease (AD) remains challenging. Here, we present a novel strategy to mitigate AD pathology by directly modulating the immune checkpoint PD-1/PD-L1 signaling pathway in the brain, where elevated levels of microglial PD-1 and astrocytic PD-L1 have been observed. We found that a single intracortical injection of anti-PD-L1 antibody facilitates the infiltration of peripheral immune cells into the brain, including IL-10-secreting Ly6C+ monocytes. Subsequently, this leads to the restoration of microglial homeostatic functions including an increase in P2RY12 expression, which enhances microglial process extension. This cascade of events following anti-PD-L1 injection is crucial for regulating abnormally hyperactive neurons and reducing amyloid-beta plaques. These findings suggest that the direct application of immune checkpoint blockade in the brain could offer a new approach to managing the delicate cell-cell interactions among neurons, glial cells, and peripheral immune cells in the AD brain.Keywords:
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Despite the significant role microglia play in the pathology of multiple sclerosis (MS), medications that act within the central nervous system (CNS) to inhibit microglia have not yet been identified as treatment options.We screened 1040 compounds with the aim of identifying inhibitors of microglia to reduce neuroinflammation.The NINDs collection of 1040 compounds, where most are therapeutic medications, was tested at 10 µM final concentration on lipopolysaccharide (LPS)-activated human microglia. An ELISA was run on the media to measure the level of TNF-α as an indicator of microglia activity. For compounds that reduce LPS-activated TNF-α levels by over 50%, considered as a potential inhibitor of interest, toxicity tests were conducted to exclude non-specific cytotoxicity. Promising compounds were subjected to further analyses, including toxicity to other CNS cell types, and multiplex assays.Of 1040 compounds tested, 123 reduced TNF-α levels of LPS-activated microglia by over 50%. However, most of these were cytotoxic to microglia at the concentration tested while 54 were assessed to be non-toxic. Of the latter, spironolactone was selected for further analyses. Spironolactone reduced TNF-α levels of activated microglia by 50-60% at 10 µM, and this concentration did not kill microglia, neurons or astrocytes. In multiplex assays, spironolactone reduced several molecules in activated microglia. Finally, during the screening, we identified 9 compounds that elevated further the TNF-α levels in LPS-activated microglia.Many of the non-toxic compounds identified in this screen as inhibitors of microglia, including spironolactone, may be explored as viable therapeutic options in MS.
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Microglia, the major inflammatory cells of the brain, play a pivotal role in the initiation and progression of Alzheimer's Disease (AD) by either phagozytosing amyloid‐β deposits or by releasing cytotoxic and pro‐inflammatory substances in response to activation by amyloid‐β aggregates, including amyloid‐β oligomers (AβO). We here propose microglial Kv1.3 channels as a novel target for curbing the harmful effects of Aβ‐induced microglia activation. Microglia isolated from the brains of adult 5xFAD mice expressed higher levels of Kv1.3 than microglia from age‐matched control mice. We further observed strong Kv1.3 immunoreactivities in microglia associated with amyloid plaques in brains of 5xFAD mice. Proof for the functional importance of Kv1.3 in microglia comes from our observations that the Kv1.3 blocker PAP‐1 inhibits AβO‐stimulated NO production as well as microglia‐mediated neurotoxicity in dissociated cultures and organotypic brain slices. A 6‐week course of daily PAP‐1 injections also reduced the degree of microglia activation in 5xFAD mice. In contrast, Kv1.3 blockade with PAP‐1 does not affect phagocytosis of Aβ aggregates by microglia. These observations suggest that Kv1.3 blockers might preferentially inhibit microglia mediated neuronal killing without affecting beneficial functions such as scavenging of debris. Supported by NIH and Alzheimer's Association
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Abstract Brain iron accumulation has been found to accelerate disease progression in amyloid-β(Aβ) positive Alzheimer patients, though the mechanism is still unknown. Microglia have been identified as key players in the disease pathogenesis, and are highly reactive cells responding to aberrations such as increased iron levels. Therefore, using histological methods, multispectral immunofluorescence and an automated in-house developed microglia segmentation and analysis pipeline, we studied the occurrence of iron-accumulating microglia and the effect on its activation state in human Alzheimer brains. We identified a subset of microglia with increased expression of the iron storage protein ferritin light chain (FTL), together with increased Iba1 expression, decreased TMEM119 and P2RY12 expression. This activated microglia subset represented iron-accumulating microglia and appeared morphologically dystrophic. Multispectral immunofluorescence allowed for spatial analysis of FTL + Iba1 + -microglia, which were found to be the predominant Aβ-plaque infiltrating microglia. Finally, an increase of FTL + Iba1 + -microglia was seen in patients with high Aβ load and Tau load. These findings suggest iron to be taken up by microglia and to influence the functional phenotype of these cells, especially in conjunction with Aβ.
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It is now generally recognized that atherosclerosis is an inflammatory disease,in which monocyte/macrophage plays a crucial role.The monocyte/macrophage is involved in every stage of atherosclerosis.The activity of monocyte/macrophage and their interactions with other cells in the plaque mileu provide novel therapeutic targets for the treatment of atherosclerosis.This paper reviews the recent advances in the treatment of atherosclerosis from those aspects of reducing monocyte/macrophage,suppressing oxidative stress, regulating cholesterol metabolism involved in monocyte/macrophage activities,decreasing macrophage-derived inflammatory activity and increasing plaque stability,to provide a reference for anti-atherosclerosis drugs' clinical use,research and development.
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Author(s): Rice, Rachel Anne | Advisor(s): Green, Kim N | Abstract: Microglia are the immune competent cells of the central nervous system (CNS). During development, microglia play critical roles in pruning synapses and refining neuronal connectivity. In the adult brain, microglia constantly survey the parenchyma for cellular damage or invading pathogens. Upon detection of such events, microglia become activated and shift to a phagocytic phenotype, secreting pro-inflammatory molecules and adopting an amoeboid morphology. As part of the resolution/repair process, microglia return to a surveillant state and produce anti-inflammatory molecules. Unfortunately, with severe insults, such as traumatic brain injury or chronic neurodegeneration, microglia remain activated and contribute to an inflammatory process that is never, or poorly, resolved. In this way, we hypothesize that microglia contribute deleteriously to functional outcomes.The goal of my dissertation is to determine the contributions of microglia to neuronal health and cognition in both the healthy and injured brain. The direct assessment of microglia-specific contributions is possible due to the discovery by our lab that microglia are dependent upon signaling through the colony-stimulating factor 1 receptor (CSF1R) for their survival. Treatment with a small-molecule CSF1R inhibitor eliminates g99% of microglia from the adult mouse brain. Critically, microglia fully repopulate the CNS upon withdrawal of the CSF1R inhibitor, effectively renewing this cellular compartment. Using a genetic model of inducible neuronal loss, I have determined that the elimination of microglia during a lesion is detrimental to cellular health, while the elimination of microglia following a lesion results in the reversal of many lesion-induced deficits. Importantly, this research suggests that the microglia-mediated immune response is beneficial during insult or injury, but deleterious after such an event. Moreover, repopulation of the brain with new microglia following neuronal lesioning largely resets the inflammatory milieu and confers functional benefits.Finally, long-term elimination of microglia was employed in order to determine if these cells shape the synaptic landscape in the healthy adult brain, as they do during development. Indeed, I found that microglial elimination in healthy adult mice results in brain-wide and robust increases in dendritic spine numbers and excitatory neuronal connectivity, indicating that microglia modulate synaptic function throughout the course of the lifetime.
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