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Cited by 142Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesTryptophan and brain disorders

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The Emerging Role of Central and Peripheral Immune Systems in Neurodegenerative Diseases

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Zang, Xin, Chen, Si, Zhu, JunYao, Ma, Junwen, Zhai, Yongzhen·2022·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2022.872134PMC PMC9082639
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Abstract

For decades, it has been widely believed that the blood–brain barrier (BBB) provides an immune privileged environment in the central nervous system (CNS) by blocking peripheral immune cells and humoral immune factors. This view has been revised in recent years, with increasing evidence revealing that the peripheral immune system plays a critical role in regulating CNS homeostasis and disease. Neurodegenerative diseases are characterized by progressive dysfunction and the loss of neurons in the CNS. An increasing number of studies have focused on the role of the connection between the peripheral immune system and the CNS in neurodegenerative diseases. On the one hand, peripherally released cytokines can cross the BBB, cause direct neurotoxicity and contribute to the activation of microglia and astrocytes. On the other hand, peripheral immune cells can also infiltrate the brain and participate in the progression of neuroinflammatory and neurodegenerative diseases. Neurodegenerative diseases have a high morbidity and disability rate, yet there are no effective therapies to stop or reverse their progression. In recent years, neuroinflammation has received much attention as a therapeutic target for many neurodegenerative diseases. In this review, we highlight the emerging role of the peripheral and central immune systems in neurodegenerative diseases, as well as their interactions. A better understanding of the emerging role of the immune systems may improve therapeutic strategies for neurodegenerative diseases.

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Crossref · 10.3389/fnagi.2022.872134

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Figure 1 Microglia perform surveillance functions of the extracellular environment of the brain in the resting state. In the presence of stressors, microglia can be activated into two states, which have been traditionally divided into M1 (classical activation) and M2 (alternative activation). Binding of receptors on microglia to Th1 cytokines drives microglia polarization to the M1 phenotype, leading to increased inflammation and oxidative stress as well as BBB dysfunction. In contrast, Th2 cytokines prompt microglia to polarize to the M2 phenotype. M2 phenotype microglia promote tissue repair and regeneration through the production of anti-inflammatory cytokines and neurotrophic factors for to exert neuroprotective effects.
Figure 1 Microglia perform surveillance functions of the extracellular environment of the brain in the resting state. In the presence of stressors, microglia can be activated into two states, which have been traditionally divided into M1 (classical activation) and M2 (alternative activation). Binding of receptors on microglia to Th1 cytokines drives microglia polarization to the M1 phenotype, leading to increased inflammation and oxidative stress as well as BBB dysfunction. In contrast, Th2 cytokines prompt microglia to polarize to the M2 phenotype. M2 phenotype microglia promote tissue repair and regeneration through the production of anti-inflammatory cytokines and neurotrophic factors for to exert neuroprotective effects.CC BY · PubMed Central
Figure 2 In pathological conditions, damaged neurons release autoantigens to activate resting microglia, which differentiate into the pro-inflammatory phenotype of M1. The M1 phenotype microglia secrete pro-inflammatory factors(IL-6, TNF-α, IFN-γ) to activate astrocytes, which induce the activation of A1 phenotype astrocytes. Reactive astrocytes contribute to the formation of glial scarring. It also leads to destruction of the BBB, which in turn leads to infiltration of CNS by peripheral immune cells. Antigens may enter peripheral lymphoid tissue, where they are presented by antigen-presenting cells to naive T cells, which differentiate into antigen-specific T effector cells (Th1, Th2, Th17 or Tregs). These cells then secrete anti-inflammatory or pro-inflammatory factors to regulate neuronal survival. Th1 and Th17 cells cross the BBB, produce neurotoxic and pro-inflammatory factors that interact with glial cells, leading directly to neuroinflammation and damage to motor neurons. Th2 and Tregs migrate from the periphery to the central nervous system and interact with glial cells to function as motor neuron protectors. In addition, antigens can directly stimulate B cells, which are activated to produce pro-inflammatory factors that travel along blood vessels to the brain and participate in neurodegeneration. Activated T cells secrete lymphokines to activate B cells, which proliferate and differentiate into plasma cells. Plasma cells can further produce cytokines and antibodies, such as anti-Aβ or anti-α-synuclein antibodies, which cross the blood-brain barrier into the brain to alleviate neuronal degeneration.
Figure 2 In pathological conditions, damaged neurons release autoantigens to activate resting microglia, which differentiate into the pro-inflammatory phenotype of M1. The M1 phenotype microglia secrete pro-inflammatory factors(IL-6, TNF-α, IFN-γ) to activate astrocytes, which induce the activation of A1 phenotype astrocytes. Reactive astrocytes contribute to the formation of glial scarring. It also leads to destruction of the BBB, which in turn leads to infiltration of CNS by peripheral immune cells. Antigens may enter peripheral lymphoid tissue, where they are presented by antigen-presenting cells to naive T cells, which differentiate into antigen-specific T effector cells (Th1, Th2, Th17 or Tregs). These cells then secrete anti-inflammatory or pro-inflammatory factors to regulate neuronal survival. Th1 and Th17 cells cross the BBB, produce neurotoxic and pro-inflammatory factors that interact with glial cells, leading directly to neuroinflammation and damage to motor neurons. Th2 and Tregs migrate from the periphery to the central nervous system and interact with glial cells to function as motor neuron protectors. In addition, antigens can directly stimulate B cells, which are activated to produce pro-inflammatory factors that travel along blood vessels to the brain and participate in neurodegeneration. Activated T cells secrete lymphokines to activate B cells, which proliferate and differentiate into plasma cells. Plasma cells can further produce cytokines and antibodies, such as anti-Aβ or anti-α-synuclein antibodies, which cross the blood-brain barrier into the brain to alleviate neuronal degeneration.CC BY · PubMed Central

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Metadata

Authors
Zang, X., Chen, S., Zhu, J., Ma, J., & Zhai, Y.
Affiliations
  • Sheng Jing Hospital (CN)
  • Fourth Affiliated Hospital of China Medical University (CN)
Corresponding author
Zhai, Yongzhen
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2022-04-25
Volume
14
Pages
872134-872134
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2022.872134
PMC
PMC9082639
OpenAlex
W4224441906
Cited by
139
References
221
Citations by year
2026: 35 · 2025: 49 · 2024: 35 · 2023: 17 · 2022: 3
FWCI
2.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
neurodegenerative diseases, neuroinflammation, blood-brain barrier, peripheral immune system, central nervous system, cytokines, microglial activation, astrocytes, immune privilege, neurodegeneration therapy

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