Looking to the Future of the Role of Macrophages and Extracellular Vesicles in Neuroinflammation in ALS
Abstract
1. Introduction
2. Immune Response Regulation and Dysregulation in the Pathogenesis of ALS
2.1. Interactions between Glial Cells Are Key Contributors to ALS Neuroinflammation Status
2.2. Microglia
2.3. Oligodendrocytes
2.4. Astrocytes
2.5. Can Peripheral Immune Cells Contribute to ALS Neuroinflammation Status?
3. Extracellular Vesicles in the Brain
4. Extracellular Vesicles, Immune Cells, and Amyotrophic Lateral Sclerosis: A Complex Paradigm
5. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gene | Locus | % fALS | Inheritance Pattern | Cellular/Molecular Effect | Clinical Phenotype |
---|---|---|---|---|---|
C9orf72 | 9p21.3 | 40–50% | Dominant | Microglia pro-inflammatory priming; Impaired regulation of autophagy and lysosomal pathways | Variable; Bulbar onset; Coincidence of frontotemporal dementia; Age-dependent penetrance |
OPTN | 10p13 | 2–3% | Dominant or recessive | Activation of the neuroinflammatory NF-kB pathway and impaired autophagy | Tendency for slower disease progression and long duration prior to respiratory dysfunction; Variable age onset |
SQSTM1 | 5q35 | ˂1% | Dominant | Autophagy and UPS degradation; Regulator of NF-kB signaling pathway; Immune response activation | Progressive weakness by loss of motor neurons |
SOD1 | 21q22 | 20–25% | Dominant or recessive | Major cytosolic antioxidant; Enhancement of microglial pro-inflammatory priming | Tendency for lower motor neuron predominance and lower limb onset; Cognitive changes are rare; Progression rate depends on SOD1 variant |
TBK1 | 12q14 | 10% | Dominant | Autophagy/proteasome impairment dysregulate the mitochondria; Induction of type-1 interferon; Removal of T cells protective regulation | Encephalopathy acute; Prevalence in European populations; Variable age of onset; Different rates of progression and survival length |
TARDBP | 1p36.2 | 4–5% | Dominant | Enhancement of microglial pro-inflammatory priming | Earlier age of onset; Upper limb onset; Longer disease onset |
VCP | 9p13 | 1–2% | Dominant | Impairment of protein degradation by the ubiquitin–proteasome pathway and autophagy | Prevalence in Caucasian populations; Tendency for limb onset; Very low bulbar and respiratory onset |
Mutation | EVs Content | Biological Involvement in Inflammation | Vesicles/Sample Type | Ref. |
---|---|---|---|---|
N.A. | miRNAs | Neural enriched fraction of exosomes Peripheral human blood from ALS patients | [120] | |
miR-451a | Inflammation reduction via TLR4 | [121] | ||
miR-15-5p | Inflammation induction via NFkB and TNIP2 | [122] | ||
miR-21-5p | Downregulation of IL-6/STAT3 pathway | [123] | ||
miR-16-5p | TNFα, IL-8, IL-6, IL-4 regulation | [124] | ||
miR-223-3p | Autophagy regulation via ATG16L1 Upregulation of IL-1β and TNFα | [125] | ||
miR-142-3p | Regulation of expression of IL-1β | [126] | ||
miR-27b-3p | Regulation of expression of IL-1β, IL-6 and TNFα | [127] | ||
SOD1 | miR-124-3p | Activation of NFkB pathway Upregulation of MMP2 and MMP9 | Mice lumbar cord tissue-derived exosomes | [128,129] |
TDP-43 | Proteins | Motor cortex exosomes Post-mortem tissues | [130] | |
CD177 | Neutrophil activation | [131] | ||
IGHV3-43 | Adaptive immunity ignition | [132] | ||
LBP | Innate immunity ignition via TLR | [133] | ||
RPS29 | Modulation of NFkB signaling | [134] | ||
S100A9 | Secretion of IL-1β, IL-6 and TNFα | [135] | ||
SAA1 | Upregulation of inflammatory mediators (CAM, MMP, cytokines, ROS, chemokines) | [136] | ||
SCAMP4 | Regulation of pro-inflammatory SASP | [137] | ||
SLC16A1 | Proliferation of CD8+ T lymphocytes | [138] | ||
N.A. | IL-6 | Pro-inflammatory cytokine | Astrocytes-derived exosomes | [139] |
C9orf72 | BLMH | Regulation of inflammatory chemokines release | CSF-derived EVs | [140] |
SOD1 | CD163 | Macrophages activation | Mice spinal cord Treg-derived EVs | [141] |
N.D. | CHIT1 | Feed-forward loop maintaining inflammation | CSF-derived EVs from patients | [142] |
SOD1 | IL-6, iNOS, IL-1 β, IFNγ | Pro-inflammatory mediators | Mice spinal cord Treg-derived EVs | [143] |
TDP-43 | TNF-R2 | Activation of pro-inflammatory protein | Patients CSF-derived EVs | [144] |
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Carata, E.; Muci, M.; Di Giulio, S.; Mariano, S.; Panzarini, E. Looking to the Future of the Role of Macrophages and Extracellular Vesicles in Neuroinflammation in ALS. Int. J. Mol. Sci. 2023, 24, 11251. https://doi.org/10.3390/ijms241411251
Carata E, Muci M, Di Giulio S, Mariano S, Panzarini E. Looking to the Future of the Role of Macrophages and Extracellular Vesicles in Neuroinflammation in ALS. International Journal of Molecular Sciences. 2023; 24(14):11251. https://doi.org/10.3390/ijms241411251
Chicago/Turabian StyleCarata, Elisabetta, Marco Muci, Simona Di Giulio, Stefania Mariano, and Elisa Panzarini. 2023. "Looking to the Future of the Role of Macrophages and Extracellular Vesicles in Neuroinflammation in ALS" International Journal of Molecular Sciences 24, no. 14: 11251. https://doi.org/10.3390/ijms241411251
APA StyleCarata, E., Muci, M., Di Giulio, S., Mariano, S., & Panzarini, E. (2023). Looking to the Future of the Role of Macrophages and Extracellular Vesicles in Neuroinflammation in ALS. International Journal of Molecular Sciences, 24(14), 11251. https://doi.org/10.3390/ijms241411251