The online version of this article (https://doi.org/10.1186/s12974-017-1003-6) contains supplementary material, which is available to authorized users.
MicroRNAs (miRNAs) play a major role in regulating immune responses at post-transcriptional levels. Previously, we have reported fluctuating interlukine-1ß (IL-1ß)/IL-10 ratios produced by peripheral blood monocytes (PBMo) in some patients with autism spectrum disorders (ASD). This study examined whether changes in miRNA expression by PBMo are associated with changes in IL-1ß/IL-10 ratios and how such changes are associated with ASD clinical features.
miRNA expression by purified PBMo from ASD subjects (N = 69) and non-ASD controls (N = 27) were determined by high-throughput sequencing. Cytokine production by PBMo in responses to stimuli of innate immunity, and behavioral symptoms [assessed by aberrant behavioral checklist (ABC)] were also evaluated at the same time of sample obtainment.
As a whole, there was no difference in miRNA expression between ASD and control non-ASD PBMo. However, when ASD cells were subdivided into 3 groups with high, normal, or low IL-1ß/IL-10 ratios as defined in the “Results” section, in comparison with the data obtained from non-ASD controls, we observed marked changes in miRNA expression. Namely, over 3-fold changes in expression of miR-181a, miR-93, miR-223, miR-342, and miR-1248 were observed in ASD PBMo with high or low IL-1ß/IL-10 ratios, but not in ASD PBMo with normal ratios. These miRNAs that had altered in expression are those closely associated with the regulation of key signaling pathways. With changes in IL-1ß/IL-10 ratios, we also observed changes in the production of cytokines (IL-6, TNF-α, and TGF-ß) other than IL-1ß/IL-10 by ASD PBMo. The association between behavioral symptoms and cytokine levels was different when ASD cells exhibit high/low IL-1ß/IL-10 ratios vs. when ASD cells exhibited normal ratios. Non-IgE-mediated food allergy was also observed at higher frequency in ASD subjects with high/low IL-1ß/IL-10 ratios than with normal ratios.
Changes in cytokine profiles and miRNA expression by PBMo appear to be associated with changes in ASD behavioral symptoms. miRNAs that are altered in expression in ASD PBMo with high/low IL-1ß/IL-10 ratios are those associated with inflammatory responses. Changes in IL-1ß/IL-10 ratios along with changes in miRNA expression may serve as biomarkers for immune-mediated inflammation in ASD.
Additional file 1: A complete list of miRNAs showing differential expression (≥ 2 fold) between groups shown in Table 2. (XLSX 11 kb)
Additional file 2: Results of Z test of miRNA expression among ASD groups and non-ASD controls cells. (XLSX 182 kb)12974_2017_1003_MOESM2_ESM.xlsx
Additional file 3: Results of Z test of miRNA expression between whole ASD cells and non-ASD control cells. (XLSX 261 kb)12974_2017_1003_MOESM3_ESM.xlsx
Additional file 4: Results of miRNA target gene analysis of group A. (XLSX 626 kb)12974_2017_1003_MOESM4_ESM.xlsx
Additional file 5: Results of miRNA target gene analysis of group B. (XLSX 543 kb)12974_2017_1003_MOESM5_ESM.xlsx
Additional file 6: Results of miRNA target gene analysis of group C. (XLSX 105 kb)12974_2017_1003_MOESM6_ESM.xlsx
Jyonouchi H. Under-recognized effects of allergic disorders on neuropsychiatric symptoms, in subjects with limited expressive language. J Clin Cell Immunol. 2016;7:413.
Jyonouchi H. Immunological abnormalities in autism spectrum disorders. Advances Neuroimmune Biol. 2013;4:141–59.
Tsujita Y, Mitsui-Sekinaka K, Imai K, Yeh TW, Mitsuiki N, Asano T, Ohnishi H, Kato Z, Sekinaka Y, Zaha K, et al. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase delta syndrome-like immunodeficiency. J Allergy Clin Immunol. 2016;138:1672–80. e1610 CrossRefPubMed
Aman MG, Singh NN, Stewart AW, Field CJ. The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic. 1985;89:485–91. PubMed
Sparrow SB Cicchetti, D.V, Vineland DV: Adaptive behavior scales survey form manual. American Guidance Service : Cirde Pines , MN 1985.
Boyce JA, Assa'ad A, Burks AW, Jones SM, Sampson HA, Wood RA, Plaut M, Cooper SF, Fenton MJ, Arshad SH, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126:S1–58. CrossRefPubMedPubMedCentral
Butrus S, Portela R. Ocular allergy: diagnosis and treatment. Ophthalmol Clin N Am. 2005;18:485–92. v
Nationa Asthma, Education, Prevention, Program. Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma—summary report 2007. J Allergy Clin Immunol. 2007;120:S94–138.
Orange JS, Ballow M, Stiehm ER, Ballas ZK, Chinen J, De La Morena M, Kumararatne D, Harville TO, Hesterberg P, Koleilat M, et al. Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2012;130:S1–24. CrossRefPubMed
Jyonouchi H, Geng L, Buyske S. Interleukin-1β/interleukin10 ratio produced by monocytes as a biomarker of neuroinflammation in autism. J Clin Cell Immunol. 2017;8:10. CrossRef
Burska A, Boissinot M, Ponchel F. Cytokines as biomarkers in rheumatoid arthritis. Mediat Inflamm. 2014;2014:545493.
Li L, Stary CM. Targeting glial mitochondrial function for protection from cerebral ischemia: relevance, mechanisms, and the role of microRNAs. Oxidative Med Cell Longev. 2016;2016:6032306.
Czimmerer Z, Varga T, Kiss M, Vazquez CO, Doan-Xuan QM, Ruckerl D, Tattikota SG, Yan X, Nagy ZS, Daniel B, et al. The IL-4/STAT6 signaling axis establishes a conserved microRNA signature in human and mouse macrophages regulating cell survival via miR-342-3p. Genome Med. 2016;8:63. CrossRefPubMedPubMedCentral
Yan XC, Cao J, Liang L, Wang L, Gao F, Yang ZY, Duan JL, Chang TF, Deng SM, Liu Y, et al. miR-342-5p is a Notch downstream molecule and regulates multiple angiogenic pathways including Notch, vascular endothelial growth factor and transforming growth factor beta signaling. J Am Heart Assoc. 2016;5
Noren Hooten N, Fitzpatrick M, Wood WH 3rd, De S, Ejiogu N, Zhang Y, Mattison JA, Becker KG, Zonderman AB, Evans MK. Age-related changes in microRNA levels in serum. Aging (Albany NY). 2013;5:725–40. CrossRef
Wang H, Zhang S, Yu Q, Yang G, Guo J, Li M, Zeng Z, He Y, Chen B, Chen M. Circulating microRNA223 is a new biomarker for inflammatory bowel disease. Medicine (Baltimore). 2016;95:e2703. CrossRef
- MicroRNA expression changes in association with changes in interleukin-1ß/interleukin10 ratios produced by monocytes in autism spectrum disorders: their association with neuropsychiatric symptoms and comorbid conditions (observational study)
Deanna L. Streck
James J. Dermody
Gokce A. Toruner
- BioMed Central