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Microglia and Monocyte-Derived Macrophages in Stroke.

ABSTRACT: Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

SUBMITTER: Kim E

PROVIDER: S-EPMC5081116 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Microglia and Monocyte-Derived Macrophages in Stroke.

Kim Eunhee E Cho Sunghee S

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20161001 4

Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especial ...[more]

PMID: 27485238

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Project description:BackgroundBoth resident microglia and invading peripheral immune cells can respond to injury and degeneration in the central nervous system. However, after dead and dying neurons have been cleared and homeostasis is re-established, it is unknown whether resident immune cells fully resume normal functions and to what degree the peripheral immune cells take up residence.MethodsUsing flow cytometry, in vivo retinal imaging, immunohistochemistry, and single-cell mRNA sequencing, we assess resident microglia and monocyte-derived macrophages in the retina during and after the loss of photoreceptors in the Arr1-/- mouse model of inducible degeneration.ResultsWe find that photoreceptor loss results in a small, sustained increase in mononuclear phagocytes and, after degeneration wanes, these cells re-establish a spatial mosaic reminiscent of healthy retinas. Transcriptomic analysis revealed the population remained unusually heterogeneous, with several subpopulations expressing gene patterns consistent with mildly activated phenotypes. Roughly a third of "new resident" cells expressed markers traditionally associated with both microglial and monocytic lineages, making their etiology ambiguous. Using an inducible Cre-based fluorescent lineage tracing paradigm to confirm the origins of new resident immune cells, we found approximately equal numbers of microglia and monocyte-derived macrophages after degeneration had subsided. In vivo retinal imaging and immunohistochemical analysis showed that both subpopulations remained functionally responsive to sites of local damage, though on average the monocyte-derived cells had less morphological complexity, expressed higher levels of MHCII, and had less migratory activity than the native resident population.ConclusionsMonocytic cells that infiltrate the retina during degeneration differentiate into monocyte-derived macrophages that can remain in the retina long-term. These monocyte-derived macrophages adopt ramified morphologies and microglia-like gene expression. However, they remain distinguishable in morphology and gene expression from resident microglia and appear to differ functionally, showing less responsiveness to subsequent retinal injuries. These findings support the idea that persistent changes in the local immune population that occur in response to cell loss in aging and progressive retinal diseases may include the establishment of subpopulations of bone marrow-derived cells whose ability to respond to subsequent insults wanes over time.

Project description:Since macrophage activation can now be studied at a global level using modern microarray and proteomic analyses, discovery of novel macrophage activation genes is inevitable and important for understanding HIV-associated dementia (HAD). We isolated two different types of primary human macrophages, microglia and monocyte-derived macrophages (MDM) from brain tissue and whole blood respectively. The microarray analysis of differentially regulated macrophage activation genes reported here supports our previous assertions that the mixed glia (MIX) cultured in starvation conditions (DMEM alone) are a non-activated, or quiescent, tissue culture model for studying macrophage activation in the brain. Transcript levels from these quiescent cultures provided a background level of gene expression, and allowed for the identification of upregulated macrophage activation genes in the MIX brain cultures upon treatment with an array of soluble activation factors: serum components, cytokines, and growth factors. We found that 914 genes in the MIX cultures and 734 genes in the MDM cultures had a greater than 2-fold increase in expression. We discovered 180 genes that were increased greater than 2 fold in both culture types. Microarray-specific statistical analyses were performed to complement fold change analysis: Significance Analysis of Microarrays (SAM), and Partek Pro. In the MIX cultures, we detected over a hundred fold increase in IL-1? and TIMP1 transcription; Caspase 9, S100A8 and 9, MMP-12, IL-8, MCP-1, MRC-1, and IL-6 were also upregulated. Activation of starved MDM cultures resulted in fewer upregulated genes compared to MIX cultures. Genes upregulated in both MIX and MDM included CCL2 (MCP1), CCL7, CXCL5, TNFSF14, kinases, and phosphatases. These microarray data may provide leads for identifying previously unknown neurotoxins, disease biomarkers, and pathways responsible for the neuronal apoptosis observed in HAD, and for the eventual identification of therapeutic targets and treatments. For each gene, we performed a per-gene normalization, whereby an expression ratio was calculated by dividing the raw data from the activated media samples by the raw signal for the same gene from the non-activated media samples (Fig. 1). The same microarray data were also analyzed again using the very common per-chip normalization method recommended by the manufacturer where raw signals for each chip were multiplied by a scaling factor such that the trimmed mean for each chip became an arbitrary number (150) (Affymetrix, 2001). The per-chip normalization method reduces person-to-person biological variability and potentially hides important changes in gene expression (Hill et al., 2001),(Bolstad et al., 2003). Therefore, we report our data using a per-gene normalization method, which yielded higher signal and low noise (uninteresting non-biological variability caused by chips, and/or experimental sample preparation), and given our experimental design, reduced person-to-person variability that these experiments cannot address directly. For later statistical analyses, the data were log transformed in order to obtain a normal distribution of the expression values of the >12,625 genes (Bolstad et al., 2003)

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Microglia and Monocyte-Derived Macrophages in Stroke.

Publications

Microglia and Monocyte-Derived Macrophages in Stroke.

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