Group I metabotropic glutamate receptor mediated dynamic immune dysfunction in children with fragile X syndrome
Open accessAbstract
BACKGROUND: Fragile X syndrome (FXS) is the leading cause of inheritable intellectual disability in male children, and is predominantly caused by a single gene mutation resulting in expanded trinucleotide CGG-repeats within the 5' untranslated region of the fragile X mental retardation (FMR1) gene. Reports have suggested the presence of immune dysregulation in FXS with evidence of altered plasma cytokine levels; however, no studies have directly assessed functional cellular immune responses in children with FXS. In order to ascertain if immune dysregulation is present in children with FXS, dynamic cellular responses to immune stimulation were examined. METHODS: Peripheral blood mononuclear cells (PBMC) were from male children with FXS (n=27) and from male aged-matched typically developing (TD) controls (n=8). PBMC were cultured for 48 hours in media alone or with lipopolysaccharides (LPS; 1 μg/mL) to stimulate the innate immune response or with phytohemagglutinin (PHA; 8 μg/mL) to stimulate the adaptive T-cell response. Additionally, the group I mGluR agonist, DHPG, was added to cultures to ascertain the role of mGluR signaling in the immune response in subject with FXS. Supernatants were harvested and cytokine levels were assessed using Luminex multiplexing technology. RESULTS: Children with FXS displayed similar innate immune response following challenge with LPS alone when compared with TD controls; however, when LPS was added in the presence of a group I mGluR agonist, DHPG, increased immune response were observed in children with FXS for a number of pro-inflammatory cytokines including IL-6 (P=0.02), and IL-12p40 (P<0.01). Following PHA stimulation, with or without DHPG, no significant differences between subjects with FXS and TD were seen. CONCLUSIONS: In unstimulated cultures, subjects with FXS did not display altered dynamic immune response to LPS or PHA alone; however, subjects with FXS showed an altered response to co-current stimulation of LPS and DHPG, such that subjects with FXS failed to inhibit production of pro-inflammatory cytokines, suggesting a role of group I mGluR signaling in innate immune responses in FXS.
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Impaired immune responses in FXS astrocytes are consistent with previously found dysregulation of several pro-inflammatory cytokines in Fmr1 KO mice and in clinical studies of FXS.
“Impaired immune responses in FXS astrocytes are consistent with previously found dysregulation of several pro-inflammatory cytokines in Fmr1 KO mice24 and in clinical studies of FXS39,53.”
From An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis (2023) · cites this paper as [53]
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- Authors
- Careaga, M., Noyon, T., Basuta, K., Van de Water, J., Tassone, F., Hagerman, R. J., & Ashwood, P.
- Affiliations
- University of California Davis Medical Center (US)
- University of California, Davis (US)
- Corresponding author
- Ashwood, Paul
- Venue
- Journal of Neuroinflammation
- Published
- 2014-06-19
- Volume
- 11
- Issue
- 1
- Pages
- 110-110
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC4107617
- OpenAlex
- W2161322144
- Cited by
- 20
- References
- 41
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 1 · 2023: 1 · 2021: 2 · 2020: 4 · 2018: 3 · 2016: 2 · 2015: 1
- FWCI
- 0.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Autism Research Institute
- Emch Foundation
- National Institutes of Health (HD02274)
- National Institute of Environmental Health Sciences (P01ES011269)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD036071, HD 02274, U54HD079125, P30HD002274, R01HD036071)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- fragile X syndrome, group I metabotropic glutamate receptors, DHPG, immune dysregulation, innate immune response, inflammatory cytokines, interleukin-6, IL-12p40, lipopolysaccharide, phytohemagglutinin, peripheral blood mononuclear cells, children, FMR1 gene, intellectual disability
- MeSH terms
- Cells, Cultured, Child, Child, Preschool, Fragile X Syndrome, Humans, Leukocytes, Mononuclear, Lipopolysaccharides, Male, Methoxyhydroxyphenylglycol, Mitogens, Phytohemagglutinins, Pyridines, Thiazoles, Case-Control Studies, Cytokines, Receptors, Metabotropic Glutamate, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, Statistics, Nonparametric, Trinucleotide Repeat Expansion, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein
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