Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism

Gupta, Saloni; Ellis, Shannon; Ashar, Foram N.; Moes, Anna; Bader, Joel S.; Zhan, Junpeng; West, Andrew B.; Arking, Dan E.

doi:10.1038/ncomms6748

Cited by 467 publications

(512 citation statements)

References 58 publications

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“…All conditions were performed in triplicate for each dataset and were repeated three times (n = 3). Significance of comparisons was determined for stimulated cells and for those cells with inhibitors/flavonoids, as denoted by the horizontal lines (P < 0.001 or P < 0.0001), and also among each of the inhibitor/flavonoid treatments shown by the horizontal brackets and by the corresponding *P < 0.05, **P < 0.001, or ***P < 0.0001. between mast cells and microglia (15,87), found to be activated in brains of patients with ASD (8)(9)(10)(11)88), is implicated in inflammation of the brain (89).…”

Section: Discussionmentioning

confidence: 99%

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Patel

Tsilioni

Leeman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

104

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We had reported elevated serum levels of the peptide neurotensin (NT) in children with autism spectrum disorders (ASD). Here, we show that NT stimulates primary human microglia, the resident immune cells of the brain, and the immortalized cell line of human microglia-SV40. NT (10 nM) increases the gene expression and release (P < 0.001) of the proinflammatory cytokine IL-1β and chemokine (C-X-C motif) ligand 8 (CXCL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 from human microglia. NT also stimulates proliferation (P < 0.05) of microglia-SV40. Microglia express only the receptor 3 (NTR3)/sortilin and not the NTR1 or NTR2. The use of siRNA to target sortilin reduces (P < 0.001) the NT-stimulated cytokine and chemokine gene expression and release from human microglia. Stimulation with NT (10 nM) increases the gene expression of sortilin (P < 0.0001) and causes the receptor to be translocated from the cytoplasm to the cell surface, and to be secreted extracellularly. Our findings also show increased levels of sortilin (P < 0.0001) in the serum from children with ASD (n = 36), compared with healthy controls (n = 20). NT stimulation of microglia-SV40 causes activation of the mammalian target of rapamycin (mTOR) signaling kinase, as shown by phosphorylation of its substrates and inhibition of these responses by drugs that prevent mTOR activation. NT-stimulated responses are inhibited by the flavonoid methoxyluteolin (0.1–1 μM). The data provide a link between sortilin and the pathological findings of microglia and inflammation of the brain in ASD. Thus, inhibition of this pathway using methoxyluteolin could provide an effective treatment of ASD.

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Section: Discussionmentioning

confidence: 99%

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Patel

Tsilioni

Leeman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

104

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“…Given their role in immune surveillance and debris clearance, it is perhaps unsurprising that microglial activation in particular has been implicated in neurodegenerative diseases beyond Alzheimer's disease, including multiple sclerosis and Parkinson's disease (Chung et al, 2015b;Heneka et al, 2015;Hong et al, 2016). As evidence accumulates positioning glia as critical for synapse maturity and elimination, many have speculated that glia and immune signaling are associated with many neuropsychiatric disorders, from stress-related conditions such as depression (Hodes et al, 2015;Miller and Raison, 2015), to neurodevelopmental disorders such as autism and schizophrenia (Gupta et al, 2014;Sekar et al, 2016;Werling et al, 2016). Here, we propose that microglia and astrocytes have an important yet largely unexplored role in the development and maintenance of drug addiction.…”

Section: Resultsmentioning

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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“…An extended transcriptome study of autism cortex also found upregulation of immune genes in autism specifically identifying increased expression of activated microglia genes. This study also identified misexpression of synaptic activity genes in autism [192]. To narrow down autism heterogeneity to the pathology of a specific development time point, cell type, and brain region, Willsey et al [193] analyzed expression data from several brain regions at many stages of development.…”

Section: Autism Genetic Studies May Point To Convergentmentioning

confidence: 93%

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

et al. 2015

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Autism spectrum disorder (ASD) is a group of highly genetic neurodevelopmental disorders characterized by language, social, cognitive, and behavioral abnormalities. ASD is a complex disorder with a heterogeneous etiology. The genetic architecture of autism is such that a variety of different rare mutations have been discovered, including rare monogenic conditions that involve autistic symptoms. Also, de novo copy number variants and single nucleotide variants contribute to disease susceptibility. Finally, autosomal recessive loci are contributing to our understanding of inherited factors. We will review the progress that the field has made in the discovery of these rare genetic variants in autism. We argue that mutation discovery of this sort offers an important opportunity to identify neurodevelopmental mechanisms in disease. The hope is that these mechanisms will show some degree of convergence that may be amenable to treatment intervention.

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Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism

Cited by 467 publications

References 58 publications

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

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

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

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