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Advanced Neurology Microglia in autism spectrum disorder

frontal cerebral cortex and that the local inflammation explored the effect of intestinal microbes on microglia-
[46]
caused by IL-8 can affect frontal cortical processing in associated neuroinflammation and found immune
these patients. The frontal cortex is critical for cognitive, abnormalities in the gastrointestinal tract of autistic
[47]
emotional, and social behavior . Its abnormal function is patients, such as increased intestinal immunoglobulin (Ig)
closely tied to the pathological mechanisms of ASD and G, intestinal CD8 lymphocyte, and T-cell infiltration in
[48]
may lead to abnormal cognitive-emotional manifestations. the mucosal lamina propria. The deposition of IgG1 and
IgG4 has been observed in the basement membrane of
IL-6 is one of the most important neuroimmune
factors that are produced over a short period of time by intestinal epithelium, along with an increased production
of TNF-α in intestinal lymphocytes. Peripheral circulating
activated microglia in response to infection and tissue immune cells may penetrate the blood-brain barrier
injury. It promotes host defense by stimulating acute (BBB) and subsequently affect neurons and glial cells,
phase, hematopoietic, and immune responses . IL-6 thereby perpetuating the immune response. Microglia
[49]
has long been shown to be associated with physiological respond to local signals within the brain and receive inputs
brain development and neurological disorders, such from the periphery, including the gastrointestinal tract.
as schizophrenia, major depression, and Alzheimer’s There is evidence showing altered microbial community
disease . Studies have shown that ASD patients have composition in nervous system diseases. Recent clinical
[50]
elevated IL-6 levels in their blood, which is strongly research has revealed that gut microbes play a critical role
associated with neuronal cell adhesion damage, migration, in regulating microglial cell maturation and function .
[56]
and synapse formation . In a study conducted by Smith However, compared with the physiological state, when
[51]
et al. , ASD-like behavioral traits were found in the mucosal rupture occurs as a result of gastrointestinal
[52]
offspring of pregnant female rats following IL-6 injection. inflammation or other factors, many intestinal bacterial-
ASD behavior was prevented by simultaneous injection related antigens, cytokines, and chemokines that damage
of anti-IL-6 antibodies in another experimental group, the BBB are released continuously. The hyperactivity of the
suggesting that IL-6 and abnormal microglia could peripheral immune system promotes CNS inflammation,
influence ASD. on which microglia are affected, thus altering the synaptic
[57]
Using the adenoviral gene delivery approach, Wei pruning of neurons and triggering ASD (Figure 2).
[53]
et al. developed a mouse model that overexpressed
IL-6 centrally and confirmed that the overexpression of 4. Therapeutic strategies targeting
IL-6 is an important mediator of autistic-like behaviors. microglia
When IL-6 levels were elevated in the brains of mice, In the previous section, we discuss the key roles microglia
autistic-like behaviors were observed. Elevated IL-6 levels play in the neuroinflammatory process of ASD. As a
have also been reported to cause abnormal changes in the dynamic cellular mediator in the CNS, microglia can
shape, length, and distribution pattern of dendritic spines, disrupt the balance of the nervous system by affecting
suggesting that elevated IL-6 levels may mediate ASD-like the microenvironment and deranging the expression of
behaviors through an imbalance of neural circuits and important neuroinflammatory molecules [27,58] . Preclinical
impairment of synaptic plasticity. In the CNS, astrocytes, assessment is anticipated to benefit from treatments
microglia, neurons, and endothelial cells of the cerebral targeting microglia dysfunction.
microvascular system are the cellular sources of IL-6, and
its levels are significantly affected by abnormal microglia 4.1. Microglia and inflammatory interventions
activation. Microglia are the primary immune cells involved in
neurodegenerative diseases of the CNS, such as ASD .
[59]
3.3. Microbial-gut-brain axis and microglia Microglia express various immune receptors that secrete
In the past few decades, the “microbial-gut-brain axis” has numerous cytokines and chemokines. The malfunctioning
garnered widespread attention from researchers , leading of these molecules in the pathologic signaling pathways of
[54]
to the discovery of the two-way communication between ASD provides neuroscientists and clinicians with potential
the gut and brain through pathways involving neural, treatment targets.
endocrine, and immune systems. Intestinal microbiota is
extensively involved in each pathway of the brain-gut axis, 4.1.1. Targeting microglia in synapse development
influencing neural development, cognition, and behavior Insufficient pruning of weak or nonfunctional synapses by
by regulating the two-way communication between the gut microglia can perturb neurodevelopment due to decreased
and the CNS. Studies have shown that gut microbes play levels of complement receptor 3 (CR3) or complement
an important role in brain function . Many studies have component 3 (C3) . Microglia regulate synaptic plasticity
[55]
[60]
Volume 1 Issue 3 (2022) 5 https://doi.org/10.36922/an.v1i3.167