The microglial sensome revealed by direct RNA sequencing

Hickman, Suzanne E.; Kingery, Nathan D.; Ohsumi, Toshiro K.; Borowsky, Mark; Wang, Li-chong; Means, Terry K.; Khoury, Joseph El

doi:10.1038/nn.3554

Cited by 1,284 publications

(1,384 citation statements)

References 58 publications

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“…Age‐related priming in microglia has been previously shown to induce a specific gene expression profile (Hickman et al ., 2013). We selected genes that were upregulated in ‘primed’ aging microglia and analyzed their expression by quantitative PCR in microglia from young (4 months), aged (24 months), G1, and G3 mTerc −/− mice (10 months).…”

Section: Resultsmentioning

confidence: 99%

“…Enhanced and persistent neuroimmune activity of microglia associated with aging is referred to as microglia priming (Perry & Holmes, 2014) and shows a unique gene expression signature (Hickman et al ., 2013). The gene expression signature of aging microglia was found to be highly similar to the profile observed in a mouse model of progressive DNA damage accumulation as a consequence of ERCC1 dysfunction, the Ercc1 mutant mice (Ercc1 Δ/− ) (Holtman et al ., 2015).…”

Section: Discussionmentioning

confidence: 99%

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Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

et al. 2015

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SummaryMicroglia are a proliferative population of resident brain macrophages that under physiological conditions self‐renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as ‘priming’. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first‐generation G1 mTerc−/−)‐ and late‐generation (third‐generation G3 and G4 mTerc−/−) telomerase‐deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late‐generation mTerc−/− microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc−/− microglia are comparable with microglia derived from G1 mTerc−/− mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc−/− microglia mice show an enhanced pro‐inflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age‐associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood–brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

et al. 2015

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“…The hypothesis that degeneration of mononuclear phagocytes is directly linked to the lack of 5-HT 2B R in this cell type is plausible for several reasons. First, Htr2b expression has been detected in newborn brain microglia [40] although it remains low in basal conditions [12,8,7,31]. Htr2b is also highly expressed in peripheral macrophages [14].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, genome-wide characterization of microglial and monocyte expression patterns led to the identification of a molecular signature of homeostatic microglia. Specifically, microglia express genes not expressed in circulating monocytes or other resident tissue macrophages such as P2ry12, Hexb, Olfml3, SiglecH, Tgfbr1 or Tmem119 [8,48,31,12,7]. Contrastingly, monocytes express surface markers not present on microglia, such as Ly6c1 [9].…”

Section: Introductionmentioning

confidence: 99%

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

et al. 2016

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Abstract:Microglia are the resident phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to overall increased phagocytic activity and production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in monocytes and microglia are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT 2B ), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT 2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT 2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT 2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT 2B mRNA in spinal cord and displayed less pronounced degeneration of mononuclear phagocytes than patients carrying two copies of the more common A allele. Thus functional 5-HT 2B receptors limit degeneration of spinal cord macrophages (most likely microglia), and slow disease progression in ALS. Targeting this receptor might be therapeutically useful.

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“…Advanced transcriptome analysis of purified cell populations in rodent cortex confirms that these other cells have transcript copies for TLR4 . In contrast, TLR2 mRNA expression is highly enriched in microglia, suggesting that some pathways of innate immune signaling are preferentially localized to discrete glial cell populations (Hickman et al, 2013;Zhang et al, 2014). Therefore, depending on the ligand, localization, MyD88 contribution, and cell type, TLR signaling can produce a wide variety of pro-and anti-inflammatory products, which may be used to communicate with multiple cell types.…”

Section: Microgliamentioning

confidence: 99%

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Lacagnina

Rivera

Bilbo

2016

Neuropsychopharmacol

223

170

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Drugs of abuse cause persistent alterations in synaptic plasticity that may underlie addiction behaviors. Evidence suggests glial cells have an essential and underappreciated role in the development and maintenance of drug abuse by influencing neuronal and synaptic functions in multifaceted ways. Microglia and astrocytes perform critical functions in synapse formation and refinement in the developing brain, and there is growing evidence that disruptions in glial function may be implicated in numerous neurological disorders throughout the lifespan. Linking evidence of function in health and under pathological conditions, this review will outline the glial and neuroimmune mechanisms that may contribute to drug-abuse liability, exploring evidence from opioids, alcohol, and psychostimulants. Drugs of abuse can activate microglia and astrocytes through signaling at innate immune receptors, which in turn influence neuronal function not only through secretion of soluble factors (eg, cytokines and chemokines) but also potentially through direct remodeling of the synapses. In sum, this review will argue that neural-glial interactions represent an important avenue for advancing our understanding of substance abuse disorders.

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The microglial sensome revealed by direct RNA sequencing

Cited by 1,284 publications

References 58 publications

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

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