Monocyte Chemotactic Protein-1 – Autism
A study published in the Journal of Neuroinflammation indicates that the chemokine monocyte chemotactic protein-1 (MCP-1) may represent an early marker for Autism Spectrum Disorders (ASD).
Immune dysregulation, dysfunctional immune profiles involving inflammatory changes in the CNS and markers of inflammation have been associated with Autism Spectrum Disorder (ASD).
For example, increased levels of inflammatory cytokine transforming growth factor beta 1 (TGFβ1), chemokine macrophage chemoattractant CCL2, and CXCL8 were found in the brains of individuals with ASD. In addition to the elevated neuroinflammatory response in the autistic brain, altered levels of circulating cytokines and chemokine have also been reported.
Also, higher levels of macrophage migration inhibitory factor (MIF) and CXCL8 were observed in plasma and cerebrospinal fluid (CSF) specimens from individuals with ASD compared with those from typically developing (TD) controls and subjects with other developmental disabilities.
In addition, elevated plasma CCL5 and CCL2 were observed in ASD, whereas increased CCL2 found newborn bloodspot specimens have been shown to be related to the risk of ASD. Similarly, altered levels of TGFβ1 have also been found in plasma and serum specimens of ASD compared with TD controls.
Increased plasma levels of MIF have been correlated with more severe social impairment and decreased imaginative play, whereas lower TGFβ1 levels have been associated with more stereotypy, irritability, hyperactivity, and other behavioral symptoms and fewer adaptive behaviors. Significant associations between increased plasma levels of CCL5 and CXCL8 and more frequent aberrant behaviors and fewer adaptive behaviors have also been found.
Yet, most of the prior studies have used specimens taken after clinical diagnosis, and even with the relatively high prevalence, currently there are no definitive predictive or diagnostic markers for ASD.
As discussed in our previous news report, cortisol variation, IL-6 and TNF-α were recently suggested as potential biomarkers for ASD.
The monocyte chemoattractant protein-1 (MCP-1/CCL2) is a member of the C-C chemokine family, and a potent chemotactic factor for monocytes. MCP-1 is believed to be identical to JE, a gene whose expression is induced in mouse fibroblasts by platelet-derived growth factor. However, the human homolog that has been best characterized as CCL2 was first purified from human cell lines on the basis of its monocyte chemoattractant properties.
CCL2 is the first discovered human CC chemokine. Located on chromosome 17 (chr.17, q11.2), human MCP-1 is composed of 76 amino acids and is 13 kDa in size. MCP belongs to a family composed of at least four members (MCP-1, −2, −3, and −4). The sequence homology between CCL2 and other family members is high and varies between 61% for CCL8 and CCL4, and 71% for CCL7.
In the Journal of Neuroinflammation study Ousseny Zerbo and colleagues from Kaiser Permanente Northern California and the University of California at Davis, CA measured cytokine and chemokine concentrations in archived neonatal blood specimens maintained by the California Department of Public Health, and from the Early Markers for Autism (EMA) population-based, nested case-control study. Newborn blood specimens were obtained by the heel-stick method, usually within 24 to 48 hours of birth.
The researchers found elevated levels of MCP-1 and decreased levels of RANTES in the newborn blood of children subsequently diagnosed with autism.
This appears to be substantiated by a recent study using amniotic fluid and reporting elevated levels of MCP-1 for children who were later diagnosed with autism.
Interestingly, MCP-1 has been implicated in neuroinflammation related to diseases characterized by neuronal degeneration. In addition, it appears to contribute to brain development and heterologous desensitization, and to influence neurotransmitter systems and pathways such as opioids, cannabinoids, etc.
Thus, if replicated in future studies, these observations may indicate that cytokine/chemokine profiling and immune system’s assessment in the first few days of life may help in the early identification of particular neurodevelopmental trajectories.
Source: J Neuroinflammation, 2014, 11:113. doi: 10.1186/1742-2094-11-113.
Read more: jneuroinflammation.com
Updates
2022
A 2022 study aimed to identify the effect of maternal exposure to high-energy dense diets, referred to as cafeteria diet (CAF) on peripheral and central proinflammatory profiles, microglia reactivity, and volumetric brain changes related to assisting defective social interaction in the mice offspring.
The authors reported a robust accumulation of the monocyte chemoattractant protein-1 (MCP-1) in plasma of ASD-diagnosed males exposed to high-energy dense diets during fetal development.
Additionally, systemic injection of MCP-1-neutralizing antibody reestablished social interaction and blocked anxiety, accompanied by a reduction in cerebellar lobule X (CbX) volume and an increase volume of the primary somatosensory (SSP) cortex in male offspring.
The authors of this study discussed that these data highlight the contribution of diet-dependent MCP-1 signaling on volumetric brain changes and microglia morphology promoting ASD-like behavior in male mice.
2024
A 2024 review discussed the hypothesis that the monocyte chemoattractant protein-1 (MCP-1) signaling is prenatally programmed to favor peripheral immune cell infiltration and activate microglia into the fetal CNS, setting susceptibility to autism-like behavior.
Background: The etiological causes of ASD have not been fully clarified; however, it is believed that the prenatal activation of the innate immune system by external stimuli might infiltrate peripheral immune cells into the fetal CNS and activate cytokine secretion by microglia and astrocytes.
The authors of this review provided the current understanding of the prenatal activation of MCP-1 signaling by external stimuli during the developmental stage as a new selective node to promote neuroinflammation, brain structural alterations, and behavioral defects associated to ASD diagnosis.
Another 2024 study reported elevated levels of interferon gamma (IFN-γ) and monocyte chemoattractant protein 1 (MCP-1) in the hippocampus, suggesting increased inflammation, alongside a reduction in the anti-inflammatory enzyme arginase 1 (ARG1). Conversely, the authors found that the prefrontal cortex (PFC) displayed reduced levels of TNF-α and MCP-1.
The investigators discussed that these region-specific changes can contribute to modulate processes like inflammation or synaptic pruning in the C58/J mouse model of idiopathic autism.
Cover Image Credit (right): MCP-1 signaling potentially affects brain function in ASD subjects. MCP-1 is found accumulated in anterior cingulate cortex, cerebellum, and cerebrospinal fluid (CSF) of ASD individuals. MCP-1 binds to a G protein‐mediated signaling cascade on the CCR2 to activate the p38 mitogen‐activated protein kinase (MAPK) and Janus kinase (JAK)/STAT3. Preclinical evidence documented that MCP-1 signaling is associated to an increase of excitatory synaptic transmission, neuroinflammation, disruption of blood–brain barrier, and immune cell recruitment into the brain of autism-like related animal models. Created by Biorender; Source: Prenatal Programming of Monocyte Chemotactic Protein-1 Signaling in Autism Susceptibility; January 2024, Molecular Neurobiology 61(8):1-16 DOI:10.1007/s12035-024-03940-z https://link.springer.com/article/10.1007/s12035-024-03940-z
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