Abstract
Autism spectrum disorder (ASD)7 is associated with multiple physiological abnormalities, including immune dysregulation, and mitochondrial dysfunction. However, an association between these two commonly reported abnormalities in ASD has not been studied in depth. This study assessed the association between previously identified alterations in cytokine profiles by ASD peripheral blood monocytes (PBMo) and mitochondrial dysfunction. In 112 ASD and 38 non-ASD subjects, cytokine production was assessed by culturing purified PBMo overnight with stimuli of innate immunity. Parameters of mitochondrial respiration including proton-leak respiration (PLR), ATP-linked respiration (ALR), maximal respiratory capacity (MRC), and reserve capacity (RC) were measured in peripheral blood mononuclear cells (PBMCs). The ASD samples were analyzed by subgrouping them into high, normal, and low IL-1ß/IL-10 ratio groups, which was previously shown to be associated with changes in behaviors and PBMo miRNA expression. MRC, RC, and RC/PLR, a marker of electron transport chain (ETC) efficiency, were higher in ASD PBMCs than controls. The expected positive associations between PLR and ALR were found in control non-ASD PBMCs, but not in ASD PBMCs. Higher MRC, RC, RC/PLR in ASD PBMCs were secondary to higher levels of these parameters in the high and normal IL-1ß/IL-10 ratio ASD subgroups than controls. Associations between mitochondrial parameters and monocyte cytokine profiles differed markedly across the IL-1ß/IL-10 ratio based ASD subgroups, rendering such associations less evident when ASD samples as a whole were compared to non-ASD controls. Our results indicate for the first time, an association between PBMC mitochondrial function and PBMo cytokine profiles in ASD subjects. This relationship differs across the IL-1ß/IL-10 ratio based ASD subgroups. Changes in mitochondrial function are likely due to adaptive changes or mitochondrial dysfunction, resulting from chronic oxidative stress. These results may indicate alteration in molecular pathways affecting both the immune system and mitochondrial function in some ASD subjects.
Highlights
Autism spectrum disorder (ASD) is defined by behavioral symptomatology which results in a heterogeneous phenotype
This study examines our hypothesis by evaluating associations between IL-1ß/IL-10 ratios produced by peripheral blood monocytes (PBMo) and variations in mitochondrial respiration in peripheral blood mononuclear cells (PBMCs), a mixture of multiple lineage cells, in ASD subjects
When mitochondrial respiration parameters were compared between all the ASD and non-ASD control samples, maximal respiratory capacity (MRC) and reserve capacity (RC) were higher in ASD cells than non-ASD controls (Figure 1)
Summary
Autism spectrum disorder (ASD) is defined by behavioral symptomatology which results in a heterogeneous phenotype. ASD is known to be associated with various comorbid medical conditions, most notably gastrointestinal (GI) symptoms, and sleep disorders [1, 2]. We have previously identified a subset of ASD subjects who exhibit innate immune abnormalities [3]. Our recent study revealed that the IL-1ß/IL-10 ratios produced by PBMo may serve as a marker of immune activation or immune mediated inflammation in individuals with ASD. Deviated IL1ß/IL-10 ratios were seen in up to 40% of ASD subjects in our previous study [4]. IL-1ß is a representative inflammatory cytokine, and IL-10 is a representative counter-regulatory cytokine. IL-1ß/IL-10 ratios are thought to reflect the balance of inflammatory vs counter-regulatory responses by monocytes
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