Heterogeneity of Neuroinflammatory Responses in Amyotrophic Lateral Sclerosis: A Challenge or an Opportunity?
Abstract
:1. Introduction
2. ALS Is a Focal Pathology, Neuroinflammatory Responses Are Intrinsically Heterogeneous
3. The Signature of Activated Microglia in ALS Is Disease Specific
4. Single-Cell and Spatial Transcriptomics Approaches: Powerful Tools to Unveil the Complexity of Neuroinflammatory Responses
5. Neuroinflammation as a Diagnostic/Prognostic Marker
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
References
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(a) Homeostatic microglia | ||||
---|---|---|---|---|
Gene | Species | CNS Regions Analyzed | Validation Methods | References |
Fcrls | Mus musculus (C57BL6) | Brain and SC | RNA-seq, RT-qPCR, IHC, FACS | [47,48,49,50] |
P2ry12 | M. musculus (C57BL6) | Brain and SC | RNA-seq, RT-qPCR, IHC, FACS | [47,49,51,52,53] |
Tmem119 | M. musculus (C57BL6) | Brain and SC | RNA-seq, RT-qPCR | [39,47,49,50,51,53] |
Tgfbr1 | M. musculus (C57BL6) | Brain and SC | RNA-seq | [47,54] |
Csfr1 | M. musculus (C57BL6) | Brain and SC | RNA-seq | [47,54] |
Sparc | M. musculus (C57BL6, DBA/2J & C57/SJL) | Brain and SC | RNA-seq, RT-qPCR | [47,55] |
Cx3cr1 | M. musculus (C57BL6, DBA/2J & C57/SJL) | Brain and SC | RNA-seq, RT-qPCR | [47,50,52,53,55] |
Hexb | M. musculus (C57BL6) | Brain and SC | RNA-seq, RT-qPCR | [47,52] |
Olfml3 | M. musculus (C57BL6) | Brain and SC | RNA-seq, RT-qPCR, IHC, FACS | [39,47,49,50] |
Ltc4s | M. musculus (C57BL6) | Brain and SC | RNA-seq | [47,50] |
SiglecH | M. musculus (C57BL6) | Brain and SC | RNA-seq, IHC, FACS | [39,47,49,51] |
Gpr34 | M. musculus (C57BL6) | Brain and SC | RT-qPCR, RNA-seq | [47,49,50] |
(b) ALS microglia | ||||
Gene | Species | CNS Regions Analyzed | Validation Methods | References |
Axl * | M. musculus (B6/SJL-SOD1G93A, C57BL6-SOD1G93A) | SC | Microarray, RNA-seq, scRNA-seq | [39,45,56] |
Apoe * | M. musculus (B6/SJL-SOD1G93A, C57BL6-SOD1G93A) | SC | Microarray, RNA-seq, scRNA-seq | [39,45,56] |
Homo sapiens (ALS patients) | Lumbar SC | RNA-seq, scRNA-seq, RT-qPCR, IHC, FACS | [45] | |
Spp1 * | M. musculus (C57BL6-SOD1G93A) | SC | RNA-seq, scRNA-seq, RT-qPCR | [39,56] |
Csf1 * | M. musculus (B6/SJL-SOD1G93A, C57BL6-SOD1G93A) | Brain and SC | Microarray, RNA-seq, scRNA-seq | [45,54] |
Cybb (Nox2) | M. musculus (C57BL6-SOD1G93A) | SC | RNA-seq, RT-qPCR, IHC | [39,40] |
Igf-1 | M. musculus (C57BL6-SOD1G93A) | SC | RNA-seq, RT-qPCR | [39] |
Grn | M. musculus (C57BL6-SOD1G93A) | SC | RNA-seq, RT-qPCR | [39] |
Optn | M. musculus (C57BL6-SOD1G93A) | SC | RNA-seq, RT-qPCR | [39] |
Mmp-12 | M. musculus (C57BL6-SOD1G93A) | SC | RNA-seq, Microarray | [39,57] |
Tyrobp * (Dap-12) | M. musculus (C57BL6-SOD1G93A) | SC | RNA-seq, scRNA-seq, RT-qPCR, ST | [39,56,58] |
H. sapiens (ALS patient) | Cervical and lumbar SC | ST | [58] | |
Trem2 * | M. musculus (C57BL6-SOD1G93A) | SC | RNA-seq, scRNA-seq, ST | [56,58] |
H. sapiens (ALS patient) | SC | ST | [58] | |
Lpl * | M. musculus (C57BL6-SOD1G93A) | SC | RNA-seq, scRNA-seq, ST | [56,58] |
H. sapiens (ALS patient) | Cervical and lumbar SC | ST | [58] | |
B2m * | M. musculus (C57BL6-SOD1G93A) | SC | RNA-seq, scRNA-seq, ST | [56,58] |
H. sapiens (ALS patient) | Cervical and lumbar SC | ST | [58] | |
Ctsl * | M. musculus (C57BL6-SOD1G93A) | SC | RNA-seq, scRNA-seq | [39,56] |
Itgax * | M. musculus (C57BL6-SOD1G93A) | Brain & SC | RNA-seq, scRNA-seq | [54,56] |
Clec7a * | M. musculus (C57BL6-SOD1G93A) | SC | RNA-seq, scRNA-seq | [39,54,56] |
(c) LPS-stimulated microglia | ||||
Gene | Species | CNS Regions Analyzed | Validation Methods | References |
Stat3 | M. musculus (C57BL6, DBA/2J and C57/SJL) | Brain and SC | RNA-seq | [39,55] |
Socs3 | M. musculus (DBA/2J and C57/SJL) | Brain | RNA-seq | [49,55,59] |
Map3k8 | M. musculus (DBA/2 J and C57/SJL) | Brain | RNA-seq | [55] |
Ccl2 | M. musculus (C57BL6) | Brain | RNA-seq | [49] |
Gpr84 | M. musculus (C57BL6) | Brain | RT-qPCR | [49,60,61] |
Tracer and Radioisotope | Target | Tested in | Notes | References |
---|---|---|---|---|
[11C]-(R)-PK11195 | TSPO | human ALS patients and healthy controls | signals are not influenced by patient’s TSPO genotype | [103,131] |
rat model of cerebral ischemia (Wistar rats) | poor specificity | |||
[18F]DPA-714 | TSPO | ALS model (SOD1G93A mouse) | signals correlate to increased TSPO expression and compromised brain regions | [87,131] |
rat model of cerebral ischemia (Wistar rats) | higher affinity and better signal-to-noise ratio than PK11195 | |||
[11C]-PBR28 | TSPO | human ALS, PLS patients and healthy controls | signals correlate to glial activation and inflammation | [102,132] |
human healthy subjects | binding is affected by TSPO polymorphism | |||
[11C]A-836339 | CB2 | neuroinflammation-induced/AD models (CD-1 and APPswe/PS1ΔE9 mouse) | first CB2 radiotracer tested | [123,124] |
AD model (APPswe/PS1ΔE9 mouse) | detection of neuroinflammation very early in the pathology | |||
[11C]NE40 | CB2 | AD, PD patients and healthy controls | no differences between disease and control cases | [127,128,133] |
ischemic stroke model (Sprague–Dawley rat) | signal in peri-infarct area, concomitant to CB2 up-regulation | |||
senescence-accelerated model (SAMP10 mouse) | detection of early signs of neuroinflammation in cortex | |||
[11C]KD2 | CB2 | ALS patients | selective binding in post-mortem ALS spinal cord specimens | [129,134] |
neuroinflammation-induced model (CD-1 mouse) | limited target specificity and excessive lipophilicity | |||
[11C]RS-016 | CB2 | neuroinflammation-induced model (CD-1 mouse) | high blood stability and CB2 specificity | [134] |
ALS patients | selective binding in post-mortem ALS spinal cord specimens | |||
[18F]29 | CB2 | neuroinflammation-induced model (CD-1 mouse) | CB2 specific tracing but very rapid metabolism | [105] |
[18F]3 | CB2 | Wistar rats | rapid washout from brain tissue | [130] |
ALS patients and healthy controls | selective binding in post-mortem ALS spinal cord specimens | |||
[11C]GSK1482160 | P2X7 | neuroinflammation-induced model (C57BL6) | increased signals in CNS sites with prominent neuroinflammation | [135] |
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Cipollina, G.; Davari Serej, A.; Di Nolfi, G.; Gazzano, A.; Marsala, A.; Spatafora, M.G.; Peviani, M. Heterogeneity of Neuroinflammatory Responses in Amyotrophic Lateral Sclerosis: A Challenge or an Opportunity? Int. J. Mol. Sci. 2020, 21, 7923. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217923
Cipollina G, Davari Serej A, Di Nolfi G, Gazzano A, Marsala A, Spatafora MG, Peviani M. Heterogeneity of Neuroinflammatory Responses in Amyotrophic Lateral Sclerosis: A Challenge or an Opportunity? International Journal of Molecular Sciences. 2020; 21(21):7923. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217923
Chicago/Turabian StyleCipollina, Giada, Arash Davari Serej, Gianluca Di Nolfi, Andrea Gazzano, Andrea Marsala, Mauro G. Spatafora, and Marco Peviani. 2020. "Heterogeneity of Neuroinflammatory Responses in Amyotrophic Lateral Sclerosis: A Challenge or an Opportunity?" International Journal of Molecular Sciences 21, no. 21: 7923. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217923