Neuroinflammation In Autism Spectrum Disorder Research Articles

Innate Immune Dysfunction and Neuroinflammation in Autism Spectrum Disorder (ASD).

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by communication and social behavior deficits. The presence of restricted and repetitive behaviors often accompanies these deficits, and these characteristics can range from mild to severe. The past several decades have seen a significant rise in the prevalence of ASD. The etiology of ASD remains unknown; however, genetic and environmental risk factors play a role. Multiple hypotheses converge to suggest that neuroinflammation, or at least the interaction between immune and neural systems, may be involved in the etiology of some ASD cases or groups. Repeated evidence of innate immune dysfunction has been seen in ASD, often associated with worsening behaviors. This evidence includes data from circulating myeloid cells and brain resident macrophages/microglia in both human and animal models. This comprehensive review presents recent findings of innate immune dysfunction in ASD, including aberrant innate cellular function, evidence of neuroinflammation, and microglia activation. Appeared originally in Brain Behav Immun 2023; 108:245-254.

Inflammatory mediators drive neuroinflammation in autism spectrum disorder and cerebral palsy

Inflammation conditions are associated with autism spectrum disorder (ASD) and cerebral palsy (CP), primarily observed in the peripheral immune system. However, the extent of neuro-inflammation and neuro-immune dysregulation remains poorly studied. In this study, we analyzed the composition of cerebrospinal fluid (CSF) to uncover the inflammatory mediators driving the neuro-immune system in ASD and CP patients. Our findings revealed that ASD patients had elevated levels of four inflammatory cytokines (TNF-α, IL-4, IL-21, and BAFF) compared to controls, while CP patients exhibited increased levels of eight inflammatory cytokines (IFN-γ, GM-CSF, TNF-α, IL-2, IL-4, IL-6, IL-17A and IL-12), one anti-inflammatory cytokine (IL-10), and five growth factors (GFs) (NGF-β, EGF, GDF-15, G-CSF and BMP-9) compared to both controls and ASD patients. Additionally, intrathecal infusion of autologous bone marrow mononuclear cells (BMMNCs) led to a slight decrease in TGF-β and GDF-15 levels in the CSF of ASD and CP patients, respectively. Our study provides new insights into the molecular composition of CSF in ASD and CP patients, with the potential to develop more effective diagnosis methods and improved treatment for these diseases.Clinical trial registration CSF samples used in this study are from clinical trials NCT03225651, NCT05307536, NCT02569775, NCT03123562, NCT02574923, NCT05472428 and previous reports [7, 9, 17–19].

A Disintegrin and Metalloproteinase Protein 8 (ADAM 8) in Autism Spectrum Disorder: Links to Neuroinflammation.

Converging lines of evidence confirmed neuroinflammation's role in autism spectrum disorder (ASD) etiological pathway. A disintegrin and metalloproteinase 8 (ADAM8) play major roles in inflammatory and allergic processes in various diseases. This study aimed to investigate ADAM8 plasma levels in autistic children compared to healthy controls. Also, to discover the association between ADAM8, disease severity, and neuroinflammation in ASD. This case-control study included children with ASD (n=40) and aged-matched healthy controls (n=40). The plasma levels of the ADAM 8 were determined using enzyme-linked immunosorbent assay (ELISA). The assessment of ASD severity and social and sensory behaviors were categorized as mild, moderate and severe. Correlations among ADAM8 plasma levels and ASD severity scores [Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS) and Short Sensory Profile (SSP)] were obtained by Spearman correlation coefficient (r). ASD children (n=40), including severe autism (n=21) and mild-to-moderate autism (n=19), showed significantly (p ≤ 0.05) lower plasma levels of ADAM8 [4683 (2885-5229); 4663 (4060-5000); 4632 (2885-5229)], respectively, than those of healthy controls [5000 (4047-5000)] [median (IQR) pg/mL]. However, there was no significant difference between the ADAM8 levels of children with severe and mild-to-moderate autism (p = 0.71). Moreover, ADAM8 plasma levels were not significantly correlated with the severity of ASD measured by behavioral scales [CARS (r= -0.11, p=0.55), SRS (r=0.11, p= 0.95), SSP (r=-0.23, p=0.23)]. The low ADAM8 plasma levels in children with ASD possibly indicated that ADAM8 might be implicated in the pathogenesis of ASD but not in the severity of the disease. These results should be interpreted with caution until additional studies are carried out with larger populations to decide whether the reduction in plasma ADAM8 levels is a mere consequence of ASD or if it plays a pathogenic role in the disease.

Cross-disease Transcriptomic Analysis Elucidating the Roles of Astrocytic Signaling Pathways Regulating Neuroinflammation in Autism Spectrum Disorder (S2.003)

<h3>Objective:</h3> This research aims to elucidate the roles of astrocytic signaling pathways regulating neuroinflammation in autism spectrum disorder. <h3>Background:</h3> While neuroinflammation has been implicated as a major component in autism spectrum disorder (ASD) and its etiology, the molecular mechanism in the disease is not well understood. Advances in single-cell genomics and transcriptomics have fueled the identification of novel pathways that control astrocyte functions associated with chronic neuroinflammatory disorders such as multiple sclerosis (MS). These advances present an opportunity to study the common molecular mechanisms involved in both ASD and MS, and ultimately elucidate ASD etiology. <h3>Design/Methods:</h3> In this paper, we analyze and characterize the common astrocytes subpopulations shared in both ASD and MS using the large-scale single-cell RNA-seq expression data collected from postmortem brain samples of subjects diagnosed with ASD (PRJNA434002) and MS (PRJNA544731). Batch correction was implemented using Harmony to strengthen the unbiased analysis. Seurat and SC3 were used for the identification of common astrocyte clusters and their marker genes; DESeq2 for disease-specific differential expressed gene (DEG) analysis; Monocle and Enrichr for trajectory and ingenuity pathway analysis (IPA) of DEGs. Finally, GSEA was performed on IPSC bulk-RNA sequencing data to further characterize the common pro-inflammatory astrocytes subpopulations using secondary progressive stage transcriptional signatures of MS. <h3>Results:</h3> This research identified two astrocyte subpopulations common to ASD and MS. Our analysis revealed that oxidative stress-mediated ferroptosis plays a pronounced role in the pathological astrocyte subpopulations. This discovery enables us to hypothesize that FTH1, SLC7A11, SAT1, CP, FTL and MAPK signaling are potentially involved in ASD pathophysiology, which could be further explored as novel targets for intervention. <h3>Conclusions:</h3> Linking transcriptionally-defined astrocyte subpopulations cross diseases could yield better understanding of their roles in each disease-specific context. Inflammation-promoting oxidative stress-mediated ferroptosis should be further studied for its roles in the pathological astrocyte subpopulations in ASD. <b>Disclosure:</b> Miss Zhang has nothing to disclose.

Photobiomodulation Attenuated Cognitive Dysfunction and Neuroinflammation in a Prenatal Valproic Acid-Induced Autism Spectrum Disorder Mouse Model.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication and interaction disorders, as well as repetitive and restrictive behaviors. To date, no effective treatment strategies have been identified. However, photobiomodulation (PBM) is emerging as a promising treatment for neurological and neuropsychiatric disorders. We used mice exposed to valproic acid (VPA) as a model of ASD and found that pathological behavioral and histological changes that may have been induced by VPA were attenuated by PBM treatment. Pregnant mice that had been exposed to VPA were treated with PBM three times. Thereafter, we evaluated the offspring for developmental disorders, motor function, hyperactivity, repetitive behaviors, and cognitive impairment. PBM attenuated many of the pathological behaviors observed in the VPA-induced ASD mouse model. In addition, pathophysiological analyses confirmed that the increase in activated microglia and astrocytes observed in the VPA-induced ASD mouse model was attenuated by PBM treatment. This suggests that PBM can counteract the behavioral changes caused by neuroinflammation in ASD. Therefore, our data show that PBM has therapeutic potential and may reduce the prevalence of neurodevelopmental disorders such as ASD.

Integration of Urine Proteomic and Metabolomic Profiling Reveals Novel Insights Into Neuroinflammation in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders whose etiology and pathogenesis are not fully understood. To gain insight into the molecular basis of ASD, we performed comparative integrated proteomic and metabolomic analyses of urine samples from children diagnosed with ASD and healthy children. All 160 samples underwent proteomics analysis and 60 were analyzed by liquid chromatography-mass spectrometry to obtain metabolite profiles. We identified 77 differentially expressed proteins (DEPs; 21 downregulated and 56 upregulated) and 277 differentially expressed metabolites; 31 of the DEPs including glutathione, leukocyte antigens, glycoproteins, neural adhesion factors, and immunoglobulins, have been implicated in neuroinflammation. The proteomic analysis also revealed 8 signaling pathways that were significantly dysregulated in ASD patients; 3 of these (transendothelial leukocyte migration, antigen processing and presentation, and graft vs. host disease) were associated with the neuroimmune response. The metabolism of tryptophan, which is also related to the neuroimmune response, has been found to play a potential role in ASD. Integrated proteome and metabolome analysis showed that 6 signaling pathways were significantly enriched in ASD patients, 3 of which were correlated with impaired neuroinflammation (glutathione metabolism, metabolism of xenobiotics by cytochrome P450 and transendothelial migration of leukocyte). We also found a correlation between prostaglandin (PG) E2 levels and the inflammatory response in ASD. These results underscore the prominent role of the neuroimmune response in ASD and provide potential biomarkers that can be used for diagnosis or as targets for early intervention.

Neuronal Cell Adhesion Molecules May Mediate Neuroinflammation in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by restrictive and repetitive behaviors, alongside deficits in social interaction and communication. The etiology of ASD is largely unknown but is strongly linked to genetic variants in neuronal cell adhesion molecules (CAMs), cell-surface proteins that have important roles in neurodevelopment. A combination of environmental and genetic factors are believed to contribute to ASD pathogenesis. Inflammation in ASD has been identified as one of these factors, demonstrated through the presence of proinflammatory cytokines, maternal immune activation, and activation of glial cells in ASD brains. Glial cells are the main source of cytokines within the brain and, therefore, their activity is vital in mediating inflammation in the central nervous system. However, it is unclear whether the aforementioned neuronal CAMs are involved in modulating neuroimmune signaling or glial behavior. This review aims to address the largely unexplored role that neuronal CAMs may play in mediating inflammatory cascades that underpin neuroinflammation in ASD, primarily focusing on the Notch, nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) cascades. We will also evaluate the available evidence on how neuronal CAMs may influence glial activity associated with inflammation. This is important when considering the impact of environmental factors and inflammatory responses on ASD development. In particular, neural CAM1 (NCAM1) can regulate NF-κB transcription in neurons, directly altering proinflammatory signaling. Additionally, NCAM1 and contactin-1 appear to mediate astrocyte and oligodendrocyte precursor proliferation which can alter the neuroimmune response. Importantly, although this review highlights the limited information available, there is evidence of a neuronal CAM regulatory role in inflammatory signaling. This warrants further investigation into the role other neuronal CAM family members may have in mediating inflammatory cascades and would advance our understanding of how neuroinflammation can contribute to ASD pathology.

Acid-Responsive Dual-Targeted Nanoparticles Encapsulated Aspirin Rescue the Immune Activation and Phenotype in Autism Spectrum Disorder.

The treatment of autism spectrum disorder (ASD) is one of the most difficult challenges in neurodevelopmental diseases, because of the unclear pathogenesis research and low brain‐lesion targeting efficiency. Besides, maternal immune activation has been reported as the most mature and widely used model of ASD and aspirin‐triggered lipoxin A4 is a potent anti‐inflammatory mediator being involved in the resolution of neuroinflammation in ASD. Therefore, an aspirin encapsulated cascade drug delivery system (Asp@TMNPs) is established, which can successively target the blood–brain barrier (BBB) and microglial cells and response to the acid microenvironment in lysosome. As a result, the mitochondrial oxidative stress, DNA damage, and inflammation of microglial cells are prominently alleviated. After the treatment of Asp@TMNPs, the social interaction, stereotype behavior, and anxious condition of ASD mice are notably improved and the activation of microglial cells is inhibited. Overall, this system successively penetrates the BBB and targets microglial cells, therefore, it significantly enhances the intracephalic drug accumulation and improves anti‐neuroinflammatory efficacy of aspirin, providing a promising strategy for ASD treatment.

Long-Lasting Changes in Glial Cells Isolated From Rats Subjected to the Valproic Acid Model of Autism Spectrum Disorder.

Synaptic alterations concomitant with neuroinflammation have been described in patients and experimental models of autism spectrum disorder (ASD). However, the role of microglia and astroglia in relation to synaptic changes is poorly understood. Male Wistar rats prenatally exposed to valproic acid (VPA, 450 mg/kg, i.p.) or saline (control) at embryonic day 10.5 were used to study synapses, microglia, and astroglia in the prefrontal cortex (PFC) at postnatal days 3 and 35 (PND3 and PND35). Primary cultures of cortical neurons, microglia, and astroglia isolated from control and VPA animals were used to study each cell type individually, neuron-microglia and microglia-astroglia crosstalk. In the PFC of VPA rats, synaptic changes characterized by an increase in the number of excitatory synapses were evidenced at PND3 and persisted until PND35. At PND3, microglia and astroglia from VPA animals were morphologically similar to those of age-matched controls, whereas at PND35, reactive microgliosis and astrogliosis were observed in the PFC of VPA animals. Cortical neurons isolated from VPA rats mimicked in vitro the synaptic pattern seen in vivo. Cortical microglia and astroglia isolated from VPA animals exhibited reactive morphology, increased pro-inflammatory cytokines, and a compromised miRNA processing machinery. Microglia from VPA animals also showed resistance to a phagocytic challenge. In the presence of neurons from VPA animals, microglia isolated from VPA rats revealed a non-reactive morphology and promoted neurite outgrowth, while microglia from control animals displayed a reactive profile and promoted dendritic retraction. In microglia-astroglia co-cultures, microglia from VPA animals displayed a reactive profile and exacerbated astrocyte reactivity. Our study indicates that cortical microglia from VPA animals are insensitive or adapted to neuronal cues expressed by neurons from VPA animals. Further, long-term in vivo microgliosis could be the result of altered microglia-astroglia crosstalk in VPA animals. Thus, our study highlights cortical microglia-astroglia communication as a new mechanism implicated in neuroinflammation in ASD; consequently, we propose that this crosstalk is a potential target for interventions in this disorder.

Humulus japonicus rescues autistic‑like behaviours inthe BTBR T+ Itpr3tf/J mouse model of autism.

Humulus japonicus (HJ) is a traditional herbal medicine that exhibits anti-inflammatory, antimicrobial and anti-tumor effects that is used for the treatment of hypertension, pulmonary disease and leprosy. Recently, it has also been reported that HJ demonstrates neuroprotective properties in animal models of neurodegenerative diseases. The current study hypothesised that the administration of HJ would exhibit therapeutic effects in autism spectrum disorder (ASD), a neurodevelopmental disorder with lifelong consequences. The BTBR T+ Itpr3tf/J mouse model of ASD was used to investigate the anti-autistic like behavioural effects of HJ. Chronic oral administration of the ethanolic extract of HJ significantly increased social interaction, attenuated repetitive grooming behaviour and improved novel-object recognition in BTBR mice. Anti-inflammatory effects of HJ in the brain were analysed using immunohistochemistry and reverse-transcription quantitative PCR analysis. Microglia activation was markedly decreased in the striatum and hippocampus, and pro-inflammatory cytokines, including C-C Motif Chemokine Ligand 2, interleukin (IL)-1β and IL-6, were significantly reduced in the hippocampus following HJ treatment. Moreover, HJ treatment normalised the phosphorylation levels of: N-methyl-D-aspartate receptor subtype 2B and calcium/calmodulin-dependent protein kinase type II subunit α in the hippocampus of BTBR mice. The results of the present study demonstrated that the administration of HJ may have beneficial potential for ameliorating behavioural deficits and neuroinflammation in ASD.

Role of Neuroinflammation in Autism Spectrum Disorder and the Emergence of Brain Histaminergic System. Lessons Also for BPSD?

Many behavioral and psychological symptoms of dementia (BPSD) share similarities in executive functioning and communication deficits with those described in several neuropsychiatric disorders, including Alzheimer’s disease (AD), epilepsy, schizophrenia (SCH), and autism spectrum disorder (ASD). Numerous studies over the last four decades have documented altered neuroinflammation among individuals diagnosed with ASD. The purpose of this review is to examine the hypothesis that central histamine (HA) plays a significant role in the regulation of neuroinflammatory processes of microglia functions in numerous neuropsychiatric diseases, i.e., ASD, AD, SCH, and BPSD. In addition, this review summarizes the latest preclinical and clinical results that support the relevance of histamine H1-, H2-, and H3-receptor antagonists for the potential clinical use in ASD, SCH, AD, epilepsy, and BPSD, based on the substantial symptomatic overlap between these disorders with regards to cognitive dysfunction. The review focuses on the histaminergic neurotransmission as relevant in these brain disorders, as well as the effects of a variety of H3R antagonists in animal models and in clinical studies.

Neuroinflammatory Gene Expression Alterations in Anterior Cingulate Cortical White and Gray Matter of Males With Autism Spectrum Disorder.

Evidence for putative pathophysiological mechanisms of autism spectrum disorder (ASD), including peripheral inflammation, blood–brain barrier disruption, white matter alterations, and abnormal synaptic overgrowth, indicate a possible involvement of neuroinflammation in the disorder. Neuroinflammation plays a role in the development and maintenance of the dendritic spines involved in glutamatergic and GABAergic neurotransmission, and also influences blood–brain permeability. Cytokines released from microglia can impact the length, location or organization of dendritic spines on excitatory and inhibitory cells as well as recruit and impact glial cell function around the neurons. In this study, gene expression levels of anti‐ and pro‐inflammatory signaling molecules, as well as oligodendrocyte and astrocyte marker proteins, were measured in both gray and white matter tissue in the anterior cingulate cortex from ASD and age‐matched typically developing (TD) control brain donors, ranging from ages 4 to 37 years. Expression levels of the pro‐inflammatory gene, HLA‐DR, were significantly reduced in gray matter and expression levels of the anti‐inflammatory gene MRC1 were significantly elevated in white matter from ASD donors as compared to TD donors, but neither retained statistical significance after correction for multiple comparisons. Modest trends toward differences in expression levels were also observed for the pro‐inflammatory (CD68, IL1β) and anti‐inflammatory genes (IGF1, IGF1R) comparing ASD donors to TD donors. The direction of gene expression changes comparing ASD to TD donors did not reveal consistent findings implicating an elevated pro‐ or anti‐inflammatory state in ASD. However, altered expression of pro‐ and anti‐inflammatory gene expression indicates some involvement of neuroinflammation in ASD. Autism Res 2020, 13: 870‐884. © 2020 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLCLay SummaryThe anterior cingulate cortex is an integral brain region in modulating social behaviors including nonverbal communication. The study found that inflammatory gene expression levels were altered in this brain region. We hypothesize that the inflammatory changes in this area could impact neuronal function. The finding has future implications in using these molecular markers to identify potential environmental exposures and distinct cell differences in autism.

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

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.

Parsing the Heterogeneity of Brain Metabolic Disturbances in Autism Spectrum Disorder

BackgroundDespite rising prevalence of autism spectrum disorder (ASD), its brain bases remain uncertain. Abnormal levels of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, or choline compounds measured by proton magnetic resonance spectroscopy suggest that neuron or glial density, mitochondrial energetic metabolism, and/or inflammation contribute to ASD neuropathology. The neuroanatomic distribution of these metabolites could help evaluate leading theories of ASD. However, most prior magnetic resonance spectroscopy studies had small samples (all <60, most <20), interrogated only a small fraction of the brain, and avoided assessing effects of age, sex, and IQ. MethodsWe acquired near-whole-brain magnetic resonance spectroscopy of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, and choline compounds in 78 children and adults with ASD and 96 typically developing children and adults, rigorously evaluating effects of diagnosis and severity on metabolites, as moderated by age, sex, and IQ. ResultsEffects of ASD and its severity included reduced levels of multiple metabolites in white matter and the perisylvian cortex and elevated levels in the posterior cingulate, consistent with white matter and social-brain theories of ASD. Regionally, both slower and faster decreases of metabolites with age were observed in ASD versus TD. Male-female metabolite differences were widely smaller in ASD than typically developing children and adults. ASD-specific decreases in metabolites with decreasing IQ occurred in several brain areas. ConclusionsResults support multifocal abnormal neuron or glial density, mitochondrial energetics, or neuroinflammation in ASD, alongside widespread starkly atypical moderating effects of age, sex, and IQ. These findings help parse the neurometabolic signature for ASD by phenotypic heterogeneity.

Modeling Inflammation in Autism Spectrum Disorders Using Stem Cells.

Recent reports show an increase in the incidence of Autism Spectrum Disorders (ASD) to 1 in every 59 children up to 8 years old in 11 states in North America. Induced pluripotent stem cell (iPSC) technology offers a groundbreaking platform for the study of polygenic neurodevelopmental disorders in live cells. Robust inflammation states and immune system dysfunctions are associated with ASD and several cell types participate on triggering and sustaining these processes. In this review, we will examine the contribution of neuroinflammation to the development of autistic features and discuss potential therapeutic approaches. We will review the available tools, emphasizing stem cell modeling as a technology to investigate the various molecular pathways and different cell types involved in the process of neuroinflammation in ASD.

Impaired lipid metabolism markers to assess the risk of neuroinflammation in autism spectrum disorder.

Autism spectrum disorder (ASD) is a multifactorial disorder caused by an interaction between environmental risk factors and a genetic background. It is characterized by impairment in communication, social interaction, repetitive behavior, and sensory processing. The etiology of ASD is still not fully understood, and the role of neuroinflammation in autism behaviors needs to be further investigated. The aim of the present study was to test the possible association between prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), prostaglandin PGE2 EP2 receptors and nuclear kappa B (NF-κB) and the severity of cognitive disorders, social impairment, and sensory dysfunction. PGE2, COX-2, mPGES-1, PGE2-EP2 receptors and NF-κB as biochemical parameters related to neuroinflammation were determined in the plasma of 47 Saudi male patients with ASD, categorized as mild to moderate and severe as indicated by the Childhood Autism Rating Scale (CARS) or the Social Responsiveness Scale (SRS) or the Short Sensory Profile (SSP) and compared to 46 neurotypical controls. The data indicated that ASD patients have remarkably higher levels of the measured parameters compared to neurotypical controls, except for EP2 receptors that showed an opposite trend. While the measured parameter did not correlate with the severity of social and cognitive dysfunction, PGE2, COX-2, and mPGES-1 were remarkably associated with the dysfunction in sensory processing. NF-κB was significantly increased in relation to age. Based on the discussed data, the positive correlation between PGE2, COX-2, and mPGES-1 confirm the role of PGE2 pathway and neuroinflammation in the etiology of ASD, and the possibility of using PGE2, COX-2 and mPGES-1 as biomarkers of autism severity. NF-κB as inflammatory inducer showed an elevated level in plasma of ASD individuals. Receiver operating characteristic analysis together with predictiveness diagrams proved that the measured parameters could be used as predictive biomarkers of biochemical correlates to ASD.

Activation of IL-17 receptor leads to increased oxidative inflammation in peripheral monocytes of autistic children

Millions of children are affected by different neurodevelopmental disorders, out of which autism spectrum disorder (ASD) poses a major hurdle to normal life style due to associated behavioral abnormalities. Several studies have shown an increased expression/release of Th17 related cytokine, IL-17A in ASD. IL-17A may enhance neuroinflammation via its IL-17A receptor, i.e. IL-17RA expressed in immune cells (such as monocytes) of autistic children. Increased oxidative stress has been implicated in a number of neuropsychiatric disorders including ASD. However, whether IL-17A/IL-17RA signaling contributes to oxidative inflammation in monocytes of autistic children has not been explored previously. With this background, we performed this study in peripheral monocytes of ASD patients and age-matched typically developing children. Our study shows that ASD individuals have increased IL-17RA expression in monocytes which is associated with increased nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway and inducible nitric oxide synthase (iNOS)/nitrotyrosine expression as compared to typically developing children. Moreover, in vitro activation of IL-17 receptor by IL-17A in monocytes isolated from ASD individuals leads to enhanced iNOS expression via NFκB pathway. IL-17RA antibody treatment in vitro reversed IL-17A-induced increase in NFκB and iNOS/nitrotyrosine expression in monocytes isolated from ASD subjects. These data connect increased IL-17A/IL-17RA signaling in ASD patients with enhanced oxidative inflammation in monocytes. Therefore, IL-17 receptor signaling in monocytes may potentiate the effects of IL-17A released by other immune cells and may aggravate neuroinflammation in ASD. Our study further suggests that blockade of IL-17A/IL-17 receptor signaling may be beneficial in the children with ASD.

Developmental microglial priming in postmortem autism spectrum disorder temporal cortex

Microglia can shift into different complex morphologies depending on the microenvironment of the central nervous system (CNS). The distinct morphologies correlate with specific functions and can indicate the pathophysiological state of the CNS. Previous postmortem studies of autism spectrum disorder (ASD) showed neuroinflammation in ASD indicated by increased microglial density. These changes in the microglia density can be accompanied by changes in microglia phenotype but the individual contribution of different microglia phenotypes to the pathophysiology of ASD remains unclear. Here, we used an unbiased stereological approach to quantify six structurally and functionally distinct microglia phenotypes in postmortem human temporal cortex, which were immuno-stained with Iba1. The total density of all microglia phenotypes did not differ between ASD donors and typically developing individual donors. However, there was a significant decrease in ramified microglia in both gray matter and white matter of ASD, and a significant increase in primed microglia in gray matter of ASD compared to typically developing individuals. This increase in primed microglia showed a positive correlation with donor age in both gray matter and white of ASD, but not in typically developing individuals. Our results provide evidence of a shift in microglial phenotype that may indicate impaired synaptic plasticity and a chronic vulnerability to exaggerated immune responses.

Neuroinflammation in Autism Spectrum Disorders: Role of High Mobility Group Box 1 Protein.

The pathogenesis of autism spectrum disorder (ASD) likely involves genetic and environmental factors, impacting the complex neurodevelopmental and behavioral abnormalities of the disorder. Scientific research studies emerging within the past two decades suggest that immune dysfunction and inflammation have pathogenic influences through different mechanisms, all leading to both a chronic state of low grade inflammation, and alterations in the central nervous system and immune response, respectively. The high mobility group box-1 protein (HMGB1) is an inflammatory marker which has been shown to play a role in inducing and influencing neuroinflammation. Current evidences suggest a possible role in the multiple pathogenic mechanisms of ASD. The aim of this manuscript is to review the major hypothesis for ASD pathogenesis, with specific regards to the immunological ones, and to provide a comprehensive review of the current data about the association between HMGB1 and ASD. A systematic search has been carried out through Medline via Pubmed to identify all original articles published in English, on the basis of the following keywords: “HMGB1”, “autism”, “autism spectrum disorder”, “neuroinflammation”, and “child”.

Immune dysfunction and neuroinflammation in autism spectrum disorder.

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder with a complex pathogenesis. Many studies over the last four decades have recognized altered immune responses among individuals diagnosed with ASD. The purpose of this critical and comprehensive review is to examine the hypothesis that immune dysfunction is present more frequently, and it is related to ASD in humans. It was found that that often individuals diagnosed with ASD have alterations in immune cells such as T cells, B cells, monocytes, natural killer cells, and dendritic cells. Also, many individuals diagnosed with ASD have alterations in immunoglobulins and increased autoantibodies. Finally, an important portion of individuals diagnosed with ASD has elevated peripheral cytokines and chemokines and associated neuroinflammation. In conclusion, immune dysregulation and inflammation are important components of ASD diagnosis and are key components of the diagnosis and treatment of ASD.