Brain IL-6 and autism

Highlights

• Aberrant neuroimmune response may contribute to phenotypic deficits of autism.

• Findings suggest that brain IL-6, a neuroimmune factor, is an important mediator of autism-like behaviors.

• A possible mechanism through which brain IL-6 elevation contributes to the development of autism is proposed.

Abstract

Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction, deficits in verbal and non-verbal communication, and repetitive behavior and restricted interests. Emerging evidence suggests that aberrant neuroimmune responses may contribute to phenotypic deficits and could be appropriate targets for pharmacologic intervention. Interleukin (IL)-6, one of the most important neuroimmune factors, has been shown to be involved in physiological brain development and in several neurological disorders. For instance, findings from postmortem and animal studies suggest that brain IL-6 is an important mediator of autism-like behaviors. In this review, a possible pathological mechanism behind autism is proposed, which suggests that IL-6 elevation in the brain, caused by the activated glia and/or maternal immune activation, could be an important inflammatory cytokine response involved in the mediation of autism-like behaviors through impairments of neuroanatomical structures and neuronal plasticity. Further studies to investigate whether IL-6 could be used for therapeutic interventions in autism would be of great significance.

Introduction

Autism is a severe neurodevelopmental disorder with a large population prevalence, characterized by impairments in social interaction, deficits in verbal and non-verbal communication, repetitive behavior and restricted interests. Although a few pharmacological treatments appear to reduce some of the associated symptoms, there are no therapeutic options that target the core symptoms of autism. Susceptibility to autism has been suggested to be attributable to genetic factors and environmental risk factors (Abrahams and Geschwind, 2008, Weiss, 2009, Buxbaum et al., 2010, Devlin et al., 2011, Hallmayer et al., 2011), however the etiology of the disorder is poorly understood. Emerging evidence suggests that aberrant neuroimmune responses may contribute to phenotypic deficits and could be appropriate targets for pharmacologic intervention (Theoharides et al., 2009, Hagberg et al., 2012, Onore et al., 2012). The neuroimmune network includes astrocytes and microglia, immune mediators as well as other classical immune pathways. The function of neuroimmune factors plays an important role in brain development and is critical for the processes of neuronal migration, axonal growth, neuronal positioning, cortical lamination, as well as dendritic and synaptic formation (Boulanger, 2009, Pardo-Villamizar and Zimmerman, 2009). Defects in neuroimmune factors could lead to neuropsychiatric disorders (McAllister and Patterson, 2012, Onore et al., 2012).

A number of studies have reported cytokine abnormalities in the peripheral blood of autistic patients (Molloy et al., 2006, Ashwood et al., 2011a, Ashwood et al., 2011b), as well as in the gastrointestinal tract (DeFelice et al., 2003, Ashwood et al., 2004). However, different research groups showed different findings on the cytokines profile in autism. We reckon these differences could be resulted from different autistic samples used and the differences in phenotype severity. In addition, the immune findings in the peripheral blood of autistic patients may not correlate with the immune-mediated pathology within the central nervous system (CNS). So far, relatively few studies concerning the expression of cytokines in the autistic brain have been conducted. Using postmortem brain specimens from autistic individuals, a study demonstrated that transforming growth factor (TGF)-β1 was significantly increased in the middle frontal gyrus of autistic patients, while macrophage chemoattractant protein (MCP)-1, Interleukin (IL)-6 and IL-10 were increased in the anterior cingulated gyrus. In addition, MCP-1, IL-6, IL-8 and Interferon (IFN)-γ were shown to be significantly increased in the cerebrospinal fluid (CSF) of autistic subjects (Vargas et al., 2005). Chez et al. has also reported the elevation of tumor necrosis factor (TNF)-α in the cerebrospinal fluid of autistic subjects (Chez et al., 2007). Most recently, Li et al. determined the activities of a set of cytokines including the pro-inflammatory cytokines [IL-6, IL-1β, TNF-α, Granulocyte–macrophage colony-stimulating factor (GM-CSF)], Th1 cytokines [IL-2, IFN-γ], Th2 cytokines (IL-4, IL-5, IL-10) and chemokine (IL-8) in the brain of autistic individuals using multiplex bead immunoassays. In this study, IL-6, TNF-α, GM-CSF, IFN-γ and IL-8 were reported to be significantly increased in the brains of autistic subjects as compared with the controls (Li et al., 2009). However, immune therapy applied to human children or adults with autism is mainly limited to a number of case reports, unpublished information, and rare case series (Chez and Guido-Estrada, 2010). Further examination of the action of drugs on cytokine profiles and how it affects autistic behaviors are of great significance.