Cytokine dysregulation – mouse model of autism
A report in the Proceedings of the National Academy of Sciences of the USA (PNAS) indicates that cellular and cytokine immune dysregulation may contribute to the autism spectrum disorder (ASD)-related behavioral deficits in a mouse model of an autism.
In March 2020 the Centers for Disease Control announced that autism affects 1 in 54 individuals under 21 living in the U.S. That’s a 10% increase in prevalence from the previous rate of 1 in 59.
And, according to the Autism Research Institute, his Executive Director, Stephen M. Edelson, Ph.D. made a statement that “This announcement once again underscores the urgent need to fund biological research on the cause of autism and potential treatments for people on the spectrum”.
Remarkably, only one year later, on December 2, 2021, the American Academy of Pediatrics reported that the autism rate rises to 1 in 44 – according to the Centers for Disease Control and Prevention (CDC), 1 in 44 children 8 years of age has been identified with a diagnosis of autism spectrum disorder.
Recent evidence indicates the involvement of an abnormal immune system activity in the pathogenesis of autism and the autism spectrum disorder (ASD). In recent reports, a higher incidence of allergy or autoimmune diseases is reported predominantly in the mothers of ASD children.
Consistent with immune involvement are findings that maternal infection is a risk factor for autism. After the 1964 rubella pandemic, 8–13% of children born to infected mothers developed features of autism. Moreover, in a study surveying all children born in Denmark from 1980 to 2005, a very significant association was found between autism and maternal viral infection during the first trimester of pregnancy.
Intriguingly, increased serum levels of interleukin (IL)-4, IL-5 and interferon (IFN)-gamma in maternal serum is associated with increased risk for ASD in the offspring, as is elevation of monocyte chemoattractant protein-1 (MCP-1) in the amniotic fluid. And, more recent study found elevated levels of MCP-1 and decreased levels of RANTES in the newborn blood of children subsequently diagnosed with autism.
In the PNAS study, Elaine Hsiao and colleagues from the California Institute of Technology, Pasadena, CA used a mouse model exhibiting many features of autism, and specifically the maternal immune activation (MIA) model.
In this model, pregnant mice were injected with synthetic, double-stranded RNA, poly(I:C), to initiate a proinﬂammatory antiviral response. Previous studies indicate that MIA induces in the offspring some major behavioral and neuro-pathological symptoms of autism, including reduced social interaction, abnormal communication and stereotyped/repetitive behavior.
The investigators found that offspring of immune-activated mothers had decreased Tregs and hyper-responsive CD4+ cells, suggesting a chronic, proinﬂammatory phenotype. This was characterized by increased IL-6 and IL-17 production by CD4+ T cells, and elevated levels of peripheral Gr-1+ CD11b+ neutrophilic and monocytic cells.
Interestingly, and as discussed by the authors, previous research indicates that increased IL-4 levels correlate with greater deﬁcits in communication, whereas high IL-8, IL-12p40, IL-6, and IL-1beta plasma levels are linked to stereotypy, hyperactivity, and lethargy scores in ASD children.
According to the authors, their observations may provide further insights into the mechanisms and relationships between brain dysfunction and altered immunity in the manifestation of abnormal behavior, and how prenatal challenges can program long-term postnatal immunity, health, and disease.
SOURCE: Proc Natl Acad Sci U S A, 2012, 109:12776. Epub 2012 Jul 16.
A 2018 study by Mohammad Mahdi Eftekharian et al. evaluated the levels of several cytokines in whole blood samples of 30 autism spectrum disorder (ASD ) patients and 41 age and sex-matched healthy subjects. The authors of this study found that TNF-α, IL-6 and IL-17 production is significantly up-regulated in ASD patients compared with healthy subjects. No significant difference has been found in expression levels of other cytokines between patients and healthy subjects.
A 2020 study by Hong-Ru Chen et al, from the University of Virginia School of Medicine, Charlottesville, Virginia combined prenatal poly(I:C)-induced maternal immune activation (MIA) and cerebral perinatal hypoxia ischemia (HI) at postnatal day 10 to form a novel, two-hit MIA/HI model. The authors compared the effects of MIA, HI, and dual-MIA/HI on synaptic density, microglial activation, monocytic infiltrates, and perineuronal nets (PNNs).
Overall, the study examined whether MIA cooperates with neonatal cerebral hypoxia ischemia to promote ASD-like aberrations in mice using a novel two-hit model.
The study found that the combination of MIA and neonatal hypoxia ischemia produces autistic-like behaviors in the offspring, and has synergistic effects in inducing neuroinflammation, monocytic infiltrates, synaptic defects, and perineuronal nets.
Of note, only the combined MIA/HI insult produces autistic-like behaviors with additional features, including monocytic infiltrates, amoeboid microglial clusters, increased PNNs, plus reduced synaptic density and the PSD-95, Homer-1, and MeCP2 expression.
Figure: Mechanism by which monocytes may induce autistic-like behaviors after MIA/HI. The authors hypothesize that prenatal infection/MIA (first-hit) sensitizes monocytes to infiltrate into the offspring brain after perinatal HI injury (second-hit). Infiltrating monocytes and their derivatives produce Otx2 and proinflammatory cytokines (e.g., TNFα) to promote PNNs and synaptic elimination, respectively, leading to impaired neural network and autistic-like behaviors. From: Monocytic infiltrates contribute to autistic-like behaviors in a two-hit model of neurodevelopmental defects by Hong-Ru Chen et al, Journal of Neuroscience 2 December 2020, 40 (49) 9386.
As per the pathologic mechanisms of MIA, the authors discussed that it is highly likely that MIA induces maternal effectors, such as IL-17α or IL-6, to directly attack the fetal brains. They speculate that via ‘epigenetic reprogramming’, the prenatal MIA may modify the “responsiveness” of monocytes or other immune cells to a secondary neonatal HI insult in offspring.
In conclusion, according to the authors, this study reveals a new role and contribution by monocytes to the onset of autistic-like behaviors after combined MIA/HI.