Microglia/Macrophages in Autoimmune Demyelinating Encephalomyelitis (Multiple Sclerosis/Neuromyelitis Optica)
Abstract
1. Introduction
2. Origins and Classification of CNS Microglia and Peripheral Macrophages
2.1. Nomenclature of Microglia and Macrophages
2.2. Fate Mapping and Origins
2.3. Surface Markers for Microglia and Macrophages
2.4. Classification via Single-Cell Analysis
3. Mechanisms of Activation and Phagocytosis Regulation in Microglia and Macrophages
3.1. Activation Pathways and Molecular Signals
3.2. Transcriptional Regulation of Functional States
3.3. Regulation of Phagocytosis
3.3.1. Phagocytosis-Promoting Molecules
3.3.2. Phagocytosis-Inhibiting Molecules
3.4. Integrated Roles in Disease and Repair
4. Interactions Between Microglia/Macrophages and Neural Cells
4.1. Interactions with Neurons
4.2. Interactions with Astrocytes
4.3. Interactions with Oligodendrocytes
4.4. Modulatory Effects on Neural Cell Functions
4.5. Microglia and Connexins (Cx)
5. Multiple Sclerosis: Disease Mechanisms and Microglia/Macrophage Involvement
5.1. Disease Overview
5.2. Animal Models of MS
5.2.1. Experimental Autoimmune Encephalomyelitis (EAE)
5.2.2. Toxin-Induced Demyelination Models
5.2.3. Viral Models
5.2.4. Transgenic Models
5.2.5. Strengths and Limitations
5.3. Roles of Microglia and Macrophages in MS Pathogenesis
5.3.1. Contribution to Inflammation and Demyelination
5.3.2. Chronic Lesion Dynamics
5.3.3. Neurodegenerative Processes
5.3.4. Role in Repair and Remyelination
5.3.5. Emerging Therapeutic Implications
5.4. Mechanisms of Action of MS Therapies Through Microglia/Macrophage Modulation
5.4.1. Anti-Inflammatory Therapies
5.4.2. Remyelination-Promoting Strategies
5.4.3. Neuroprotection and Microglial Modulation
5.4.4. Emerging Therapies
5.4.5. Limitations and Future Directions
6. Neuromyelitis Optica: Disease Mechanisms and Microglia/Macrophage Involvement
6.1. Disease Overview
6.2. Animal Models of NMOSD
6.2.1. Passive Transfer Models
6.2.2. Active Immunization Models
6.2.3. Limitations of Current Models
6.2.4. Advances in Model Development
6.3. Roles of Microglia and Macrophages in NMOSD Pathogenesis
6.3.1. Microglial Activation in NMOSD
6.3.2. Macrophage Recruitment and Activation
6.3.3. Complement-Mediated Effects
6.4. Therapeutic Agents for NMOSD and Their Effects on Microglia and Macrophages
6.4.1. Complement Inhibition
6.4.2. IL-6 Receptor Blockade
6.4.3. B-Cell Depletion Therapies
6.4.4. Intravenous (IV)Ig Therapy
6.4.5. Steroid Pulse Therapy
6.4.6. Plasma Exchange
6.4.7. Emerging Therapeutic Targets
6.4.8. Mechanistic Insights
7. Similarities and Differences in Microglial and Macrophage Actions in MS and NMOSD
7.1. Similarities
7.1.1. Pro-Inflammatory Activation
7.1.2. BBB Disruption
7.1.3. Phagocytosis and Debris Clearance
7.1.4. Complement Activation
7.1.5. Dual Role in Pathogenesis and Repair
7.2. Differences
7.2.1. Primary Targets of Damage
7.2.2. Role of Complement
7.2.3. Inflammatory Profile
7.2.4. Recruitment of Peripheral Macrophages
7.2.5. Disease-Specific Phenotypes
7.2.6. Therapeutic Implications
7.3. Clinical Implications
8. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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Cell Type | State | Surface Markers | Features/Functions |
---|---|---|---|
Microglia | Steady state | TMEM119, P2RY12, CX3CR1 | Surveillance of the CNS, neuroprotection, and synaptic remodeling |
Activated state | MHC class II, CD68, CD86 | Antigen presentation, secretion of pro-inflammatory cytokines, neurotoxicity | |
Macrophages | Steady state | CD45 (high expression), CD68, CD206 | Antigen presentation, immune surveillance, and tissue repair |
Activated state | M1-like: CD86, iNOS | Pro-inflammatory, pathogen clearance, tissue destruction | |
M2-like: CD206, Arginase-1 | Anti-inflammatory, tissue repair, resolution of inflammation |
Disease | Model Name | Key Features | References |
---|---|---|---|
MS | EAE (Experimental Autoimmune Encephalomyelitis) | T cell-mediated inflammation and demyelination; most widely used MS model | [27] |
Cuprizone Model | Oligodendrocyte toxicity-induced demyelination; models remyelination | [28] | |
Lysolecithin Model | Localized demyelination via lipid disruption; used for focal lesion studies | [29] | |
TMEV (Theiler’s Murine Encephalomyelitis Virus) Model | Virus-induced chronic demyelination; models progressive MS | [30] | |
Transgenic MOG-TCR Model | Spontaneous MS-like autoimmunity; models T cell responses | [31] | |
NMO | Passive Transfer Model | AQP4-IgG transfer induces astrocyte injury; requires BBB disruption | [32] |
Active Immunization Model | AQP4 peptide immunization mimics chronic inflammation | [33] | |
Intrathecal AQP4-IgG Model | Direct administration of AQP4-IgG and complement; astrocytopathy model | [34] | |
CD59-Knockout Model | Complement regulatory deficiency increases AQP4-IgG pathology | [34] |
Disease | Drug | Mechanism of Action |
---|---|---|
MS | Ocrelizumab | Anti-CD20 monoclonal antibody; B-cell depletion |
Natalizumab | Anti-α4 integrin monoclonal antibody; inhibits immune cell migration | |
Fingolimod | S1P receptor modulator; prevents lymphocyte egress | |
Siponimod | Selective S1P1/S1P5 modulator; reduces neuroinflammation | |
Tolebrutinib | BTK inhibitor; suppresses microglial activation | |
Clemastine fumarate | Promotes OPC differentiation and remyelination | |
Masitinib | Tyrosine kinase inhibitor; reduces microglial activation | |
NMO | Eculizumab | C5 complement inhibitor; prevents complement-mediated astrocyte injury |
Satralizumab | IL-6 receptor antagonist; reduces pro-inflammatory signaling | |
Inebilizumab | Anti-CD19 monoclonal antibody; depletes B cells | |
Rituximab | Anti-CD20 monoclonal antibody; depletes B cells | |
IVIg | Modulates Fc receptor activation; reduces inflammation | |
PLEX | Removes pathogenic autoantibodies and immune complexes | |
CSF1R inhibitors | CSF1R blockade; reduces microglial/macrophage activation |
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Yamasaki, R. Microglia/Macrophages in Autoimmune Demyelinating Encephalomyelitis (Multiple Sclerosis/Neuromyelitis Optica). Int. J. Mol. Sci. 2025, 26, 3585. https://doi.org/10.3390/ijms26083585
Yamasaki R. Microglia/Macrophages in Autoimmune Demyelinating Encephalomyelitis (Multiple Sclerosis/Neuromyelitis Optica). International Journal of Molecular Sciences. 2025; 26(8):3585. https://doi.org/10.3390/ijms26083585
Chicago/Turabian StyleYamasaki, Ryo. 2025. "Microglia/Macrophages in Autoimmune Demyelinating Encephalomyelitis (Multiple Sclerosis/Neuromyelitis Optica)" International Journal of Molecular Sciences 26, no. 8: 3585. https://doi.org/10.3390/ijms26083585
APA StyleYamasaki, R. (2025). Microglia/Macrophages in Autoimmune Demyelinating Encephalomyelitis (Multiple Sclerosis/Neuromyelitis Optica). International Journal of Molecular Sciences, 26(8), 3585. https://doi.org/10.3390/ijms26083585