Serum microRNAs in ASD: Association With Monocyte Cytokine Profiles and Mitochondrial Respiration

Abstract

Our previous research has shown that purified peripheral blood monocytes (PRMo) from individuals who are diagnosed with autism spectrum disorders (ASDs) and have innate immune abnormalities reveal altered interleukin-1ß (IL-1ß)/IL-10 ratios. We also found, in separate studies, that microRNA (miRNA) expression in PBMo and mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) differed in the IL-1ß/IL-10-based ASD subgroups. This study explored whether serum miRNAs are associated with both altered innate immune responses and changes in mitochondrial respiration as a link of regulatory mechanisms for these two common abnormalities in ASD subjects. Serum miRNA levels were examined by high-throughput deep sequencing in ASD and non-ASD control sera with concurrent measurement of PBMo cytokine production and mitochondrial respiration by PBMCs. ASD samples were examined as a whole group and with respect to the previously defined IL-1ß/IL-10-based ASD subgroups (high, normal, and low groups). Serum miRNA levels differed between the overall ASD sera (N = 116) and non-ASD control sera (N = 35) and also differed across the IL-1ß/IL-10-based ASD subgroups. Specifically, miRNA levels were increased and decreased in eight and nine miRNAs, respectively, in the high-ratio ASD subgroup (N = 48). In contrast, the low- (N = 25) and normal- (N = 43) ratio ASD subgroups only showed decreased miRNAs levels (18 and 10 miRNAs, respectively). Gene targets of the altered miRNAs in the high and/or low IL-1β/IL-10 ratio ASD subgroups were enriched in pathways critical for monocyte functions and metabolic regulation. Gene targets of the altered miRNAs in all the ASD subgroups were enriched in pathways of neuronal development and synaptic plasticity, along with cell proliferation/differentiation. ASD subgroup-specific associations were observed between serum miRNA expression and IL-1ß/IL-10 ratios, mitochondrial respiration, and monocyte cytokine profiles (IL-10, CCL2, and TNF-α). In summary, our results indicate that serum levels of select miRNAs may serve as promising biomarkers for screening and monitoring changes in innate immunity and mitochondrial respiration in ASD.

Comprehensive circRNA Expression Profile and Construction of circRNAs-Related ceRNA Network in a Mouse Model of Autism

“…In the serum of individuals with autism, 13 miRNAs were differentially expressed, some of which showed diagnostic potential for patients with autism (Mundalil Vasu et al, 2014 ). Subsequent research achieved similar results, that serum miRNAs may be promising biomarkers for autism (Kichukova et al, 2017 ; Jyonouchi et al, 2019 ). Besides, 14 miRNAs were identified differentially expressed in salivary samples from autism patients, and most of them significantly correlate with Vineland neurodevelopmental scores, including miR-27a, miR-23a, and miR-628-5p (Hicks et al, 2016 ).…”

“…Circulating miRNAs were aberrantly expressed in autism individuals compared with that in controls (Mundalil Vasu et al, 2014 ; Hicks et al, 2016 ; Jyonouchi et al, 2019 ). In the serum of individuals with autism, 13 miRNAs were differentially expressed, some of which showed diagnostic potential for patients with autism (Mundalil Vasu et al, 2014 ).…”

Subanesthetic ketamine rapidly alters medial prefrontal miRNAs involved in ubiquitin-mediated proteolysis

“…Two mice were used per group according to previous studies with microarray analysis [ 28 , 29 ]. Raw data value over 5 was selected for stable analysis based on a previously published paper [ 30 ]. To further reduce false positives in the microarray data analysis, miRNAs with fold change lower than 10% were excluded.…”

Systematic Review and Bioinformatic Analysis of microRNA Expression in Autism Spectrum Disorder Identifies Pathways Associated With Cancer, Metabolism, Cell Signaling, and Cell Adhesion

“…Six studies did not provide the ASD diagnostic criteria but did report that the participants had ASD, including autistic disorder, Asperger's disorder, and pervasive developmental disorder-not otherwise specified (PDD-NOS) (10,14,18,33,35,53); thus, they are included in this study. Ten of these studies involved brain tissue (10)(11)(12)(13)(14)(15)(16)(17)(18)53), 15 involved peripheral blood (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), four employed lymphoblastoid cell lines (34-37), three examined saliva (38)(39)(40), 1 examined reprogrammed induced pluripotent stem cell-derived neurons (41), and 1 examined olfactory mucosal stem cells and skin fibroblasts (42). Variation in these studies is due to differences in the patients investigated, the tissue examined, microRNA profiling and analysis methods, the number of samples, and the statistical analysis approach used.…”

“…Since the first study performed by Abu-Elneel and his colleagues in 2008 (10), miRNA expression profiling in ASD has been performed in brain tissue samples (10)(11)(12)(13)(14)(15)(16)(17)(18), serum (19)(20)(21)(22)(23), blood (24)(25)(26)(27)(28)(29)(30), peripheral blood monocytes (31)(32)(33), lymphoblast cell lines (34)(35)(36)(37), saliva (38)(39)(40), reprogrammed induced pluripotent stem cell-derived neurons (41), olfactory mucosal stem cells, and skin fibroblasts (42) in studies comparing ASD persons and controls. There were a significant number of miRNAs in ASD samples and control with different expressions; however, many discrepancies among studies exist.…”