Aberrant NF-KappaB Expression in Autism Spectrum Condition: A Mechanism for Neuroinflammation

Abstract

Autism spectrum condition (ASC) is recognized as having an inflammatory component. Post-mortem brain samples from patients with ASC display neuroglial activation and inflammatory markers in cerebrospinal fluid, although little is known about the underlying molecular mechanisms. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein found in almost all cell types and mediates regulation of immune response by inducing the expression of inflammatory cytokines and chemokines, establishing a feedback mechanism that can produce chronic or excessive inflammation. This article describes immunodetection and immunofluorescence measurements of NF-κB in human post-mortem samples of orbitofrontal cortex tissue donated to two independent centers: London Brain Bank, Kings College London, UK (ASC: n = 3, controls: n = 4) and Autism Tissue Program, Harvard Brain Bank, USA (ASC: n = 6, controls: n = 5). The hypothesis was that concentrations of NF-κB would be elevated, especially in activated microglia in ASC, and pH would be concomitantly reduced (i.e., acidification). Neurons, astrocytes, and microglia all demonstrated increased extranuclear and nuclear translocated NF-κB p65 expression in brain tissue from ASC donors relative to samples from matched controls. These between-groups differences were increased in astrocytes and microglia relative to neurons, but particularly pronounced for highly mature microglia. Measurement of pH in homogenized samples demonstrated a 0.98-unit difference in means and a strong (F = 98.3; p = 0.00018) linear relationship to the expression of nuclear translocated NF-κB in mature microglia. Acridine orange staining localized pH reductions to lysosomal compartments. In summary, NF-κB is aberrantly expressed in orbitofrontal cortex in patients with ASC, as part of a putative molecular cascade leading to inflammation, especially of resident immune cells in brain regions associated with the behavioral and clinical symptoms of ASC.

Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids

“…This suggests that there could be a role for inflammatory pathways in the pathobiology of autism. This is supported by the observation that patients with autism have increased plasma-circulating levels of proinflammatory cytokines [31][32][33][34]. Because acetylcholine suppresses proinflammatory cytokine production and the cholinergic system is altered in autism, it is likely that maternal infections (clinical or subclinical) induced elevation in IL-6 and TNF-a evoke fetal brain injury that could lead to changes in gene expression patterns into the neonatal period.…”

Evidence of activation of the Toll-like receptor-4 proinflammatory pathway in patients with schizophrenia

“…36 In accordance with our results, NF-κB upregulation had previously been found in the postmortem PFC of patients with schizophrenia and in patients with other psychiatric diseases, such as depression or autism. [37][38][39] Recently, meta-analysis of gene coexpression networks in the postmortem PFC of patients with schizophrenia and controls found quantitative and clustering alterations in the module including immunity-related genes, such as TLR2, CD14, MYD88 and NFKBIA. 40 Previous studies demonstrated a peripheral imbalance in the TLR4 signalling pathway in patients with schizophrenia.…”

Refinement of schizophrenia GWAS loci using methylome-wide association data

“…We observed that methylation block at ATXN7 overlaps with transcription factor binding sites (Table S2) where RELA (NF-kappa-B) binds. NF-kappa-B protein mediates the regulation of immune response and its abnormal expression is associated with Autism spectrum condition (ASC) (Young et al 2011), characterized as having an inflammatory component.…”