Plasma peroxiredoxin changes and inflammatory cytokines support the involvement of neuro-inflammation and oxidative stress in Autism Spectrum Disorder

P M Abruzzo,P Visconti,L De Franceschi,A Bolotta,A Siciliano,A Ghezzo,M Marini,A Matté,E Federti,A Posar,T Guarnieri

doi:10.1186/s12967-019-2076-z

Abstract

BackgroundIt has been established that children with Autism Spectrum Disorders (ASD) are affected by oxidative stress, the origin of which is still under investigation. In the present work, we evaluated inflammatory and pro-oxidant soluble signature in non-syndromic ASD and age-matched typically developing (TD) control children.MethodsWe analyzed leukocyte gene expression of inflammatory cytokines and inflammation/oxidative-stress related molecules in 21 ASD and 20 TD children. Moreover, in another—comparable—group of non-syndromic ASD (N = 22) and TD (N = 21) children, we analyzed for the first time the protein expression of the four members of the antioxidant enzyme family of peroxiredoxins (Prx) in both erythrocyte membranes and in plasma.ResultsThe gene expression of IL6 and of HSP70i, a stress protein, was increased in ASD children. Moreover, gene expression of many inflammatory cytokines and inflammation/oxidative stress-related proteins correlated with clinical features, and appeared to be linked by a complex network of inter-correlations involving the Aryl Hydrocarbon Receptor signaling pathway. In addition, when the study of inter-correlations within the expression pattern of these molecules was extended to include the healthy subjects, the intrinsic physiological relationships of the inflammatory/oxidative stress network emerged. Plasma levels of Prx2 and Prx5 were remarkably increased in ASD compared to healthy controls, while no significant differences were found in red cell Prx levels.ConclusionsPrevious findings reported elevated inflammatory cytokines in the plasma of ASD children, without clearly pointing to the presence of neuro-inflammation. On the other hand, the finding of microglia activation in autoptic specimens was clearly suggesting the presence of neuro-inflammation in ASD. Given the role of peroxiredoxins in the protection of brain cells against oxidative stress, the whole of our results, using peripheral data collected in living patients, support the involvement of neuro-inflammation in ASD, and generate a rational for neuro-inflammation as a possible therapeutic target and for plasma Prx5 as a novel indicator of ASD severity.

Highlights

It has been established that children with Autism Spectrum Disorders (ASD) are affected by oxidative stress, the origin of which is still under investigation
Pro‐inflammatory signature characterizes peripheral blood mononuclear cells from ASD patients Gene expression of cytokines and inflammation/oxidation-related molecules was examined in Peripheral blood mononuclear cells (PBMC) from the first group of ASD and typically developing (TD) children
Comparisons between the ASD and the TD group of children revealed significant differences in the leukocyte expression of IL6, a major inflammatory cytokine, and of HSP70i, perhaps the most important chaperon involved in cellular defense mechanisms

Summary

Introduction

It has been established that children with Autism Spectrum Disorders (ASD) are affected by oxidative stress, the origin of which is still under investigation. ASD has a strong genetic basis [4, 5], with over 100 identified monogenic syndromes [6], a high number of susceptibility genes, of copy number variation (CNV) loci, and of rare genetic mutations/variants; genetics alone accounts to only 30–35% of ASD cases [7]. Non-syndromic ASD appears as a complex genetic trait, resulting from the combination of multiple de novo mutations, CNV, rare genetic variants and epigenetic regulation, with possible additive effects. Such etiological complexity forms the basis of the heterogeneity of the disease and challenges the attempts of finding therapeutic solutions

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