Exosomes, mitochondrial DNA and microglia: the fateful triangle in autism

Autism Spectrum Disorder (ASD) remains without distinct pathogenesis and effective treatment. Extracellular vesicles (EVs or exosomes) are secreted in blood or other biological fluids by diverse cell types

EVs are generated either from the cell when multivesicular bodies (MVBs) fuse with the plasma membranes or they are released directly from the plasma membrane.3 EVs can be isolated from serum, plasma, urine and other biological fluids and have been shown to contain RNA, DNA, lipids or proteins that are delivered to the surrounding cells or carried to distal sites. EVs have been implicated in brain disorders, but their presence in ASD has not been investigated.

We isolated EVs from children with ASD (n=20, 4-12 years old), and total EV-associated protein was increased as compared (P less than 0.022) to age and sex-matched normotypic controls (n=10). Moreover, EVs isolated from serum of patients with ASD stimulated cultured human microglia to secrete (184.3 ± 7.62 pg/mL, p less than0.0001) the pro-inflammatory cytokine interleukin IL-1β.The source or cargo of the EVs isolated from the serum of children with ASD is not presently known.  Exosomes could come from peripheral immune cells, such as mast cells,and could cross the blood-brain-barrier. Alternatively, astrocytes and glioblastoma cells were reported to secrete exosomes containing mitochondrial DNA (mtDNA). We showed that mast cells secrete mtDNA, some of which is inside exosomes, and we further reported that mtDNA is increased in the serum of children with ASD. Extracellular mtDNA would act a an “innate pathogen” and trigger a stong auto-inflammatory response. Given that food allergies, asthma and atopic dermatitis, which involve mast cells, have been associated with ASD, EVs could also contain known mast cell-derived microglia triggers such histamine and tryptase or neurotensin. They could even contain autoantibodies against brain epitopes. These findings suggest a possible link between EVs and inflammation of the brain and indicate a novel pathogenetic mechanism that may also be used for objective diagnosis, or targeted for the treatment of ASD.

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