Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis

Masi, Anne; Quintana, Daniel; Glozier, Nick; Lloyd, Andrew R.; Guastella, Adam J.

doi:10.1038/mp.2014.59

Cited by 374 publications

(281 citation statements)

References 71 publications

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“…Stimulation with NT (nM) increases gene expression and release of the proinflammatory cytokine IL-1β and chemokines CXCL8, CCL2, and CCL5, relevant to ASD. Increased levels of these mediators have been reported in the brains (8,19) and blood (57,58) of patients with ASD, as well as in mice with autistic-like behavior (59).…”

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.

103

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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.

103

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“…Innate immunity, therefore, plays a fundamental role in ASD development. Innate immunity-related cytokines and chemokines are altered in ASD compared with controls, and suggest these molecules may be used as ASD risk immune markers (Zerbo et al 2014, Masi et al 2015, Xu et al 2015. Alternative mRNA splicing disorder in ASD may explain some impairment in monocyte/macrophage and natural killer cells (Stamova et al 2013).…”

Section: Peripheral Monocluate Cellsmentioning

confidence: 99%

Immune dysfunction and neuroinflammation in autism spectrum disorder

Bjørklund

Saad

Chirumbolo

et al. 2016

Acta Neurobiologiae Experimentalis

137

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“…Since signs of subchronic systemic (and central) inflammation are often present in at least a subset of patients with neurodevelopmental disorders (64,86,92,101,150), considerable research has been undertaken to address the question of whether maternal exposure to infectious or inflammatory agents may lead to persistent inflammatory changes in the offspring postnatally. The evidence for this hypothesis is, at best, equivocal.…”

Section: Peripheral (And Central) Inflammationmentioning

confidence: 99%

Long-term pathological consequences of prenatal infection: beyond brain disorders

Labouesse

Langhans

Meyer

2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis

Cited by 374 publications

References 71 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

Immune dysfunction and neuroinflammation in autism spectrum disorder

Long-term pathological consequences of prenatal infection: beyond brain disorders

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