An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in rd10 Mice
Abstract
:1. Introduction
2. Materials and Methods
2.1. Mechanistic Modeling of the Relevance of ELOVL4 and ALOX5 on an RP Mechanistic Map
2.2. EFA Supplement Manufacturing Process
2.3. Cell Culture of 661W and BV2
2.4. Cell Viability
2.5. Synthesis of Coumarin-6-Loaded Nanostructured Lipid Carriers (NLC) and the Internalization Study
2.6. Immnunocytochemistry
2.7. Animals and Treatment
2.8. Electroretinogram
2.9. Light/Dark Transition Test
2.10. Retinal Histology
2.11. Microscopy and Quantification
2.12. Gene Expression
2.13. Flow Cytometry of Retinal Tissue
2.14. Enzyme-Linked Immunosorbent Assay of TNFα
2.15. Determination of Redox Status
2.16. Statistical Analysis
3. Results
3.1. ALOX5 and ELOVL4 Relevance in the RP Mechanistic Map Obtained by the ML Model
3.2. Altered Temporal Profile of Alox5, Alox8, Alox1, and Elovl4 in the Retinas of rd10 Mice
3.3. SPM Precursors Shifted M1 Microglia to M2 in LPS-Treated BV2 Cells
3.4. Oral Administration of SPM Precursors Ameliorated Retinal Dysfunction and Reduced PR Degeneration in rd10 Mice
3.4.1. ERG Recordings
3.4.2. Light Aversion
3.4.3. PR Degeneration
3.5. Oral Administration of SPM Precursors Reduced Reactive Gliosis, Microglia Migration, and M1-Microglia Markers and Increases M2-Microglia Markers in rd10 Mouse Retinas at P18
3.5.1. Reactive Gliosis and Iba1-Positive Cell Migration
3.5.2. M1 and M2 Microglia Markers
3.6. Oral Administration of SPM Precursors Ameliorated Oxidative Stress in rd10 Mouse Retinas at P18
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Fatty Acid | g/100 g | |
---|---|---|
Palmitic | C16:0 | 0.47 |
Palmitoleic | C16:1 n7 | 0.28 |
Hexadecaenoic | C16:4 n1 | 0.09 |
Stearic | C18:0 | 0.78 |
Oleic | C18:1 n9 | 1.24 |
Vaccenic | C18:1 n7 | 0.51 |
Linoleic | C18:2 n6 | 0.19 |
Linolenic | C18:3 n3 | 0.11 |
Stearidonic | C18:4 n3 | 0.43 |
Arachidic | C20:0 | 1.44 |
Eicosenoic | C20:1 n9 | 2.78 |
Gondonic | C20:1 n7 | 0.38 |
Arachidonic | C20:4 n6 | 1.05 |
Eicosatetraenoic | C20:4 n3 | 1.15 |
Eicosapentaenoic | C20:5 n3 | 18.36 |
Behenic | C22:0 | 1.44 |
Erucic | C22:1 n11 | 2.78 |
Adrenic | C22:4 n6 | 0.46 |
Docosapentaenoic | C22:5 n6 | 0.90 |
Docosapentaenoic | C22:5 n3 | 6.81 |
Lignoceric | C24:0 | 0.44 |
Docosahexaenoic | C22:6 n3 | 40.73 |
Nervonic | C24:1 n9 | 2.17 |
Total ω3 | 67.59 | |
Total ω6 | 2.14 | |
Total ω9 | 6.19 | |
SFAs | 4.57 | |
MUFAs | 10.14 | |
PUFAs | 69.13 |
Fatty Acid | mg/g of Body Weight |
---|---|
Palmitic | 0.013 |
Palmitoleic | 0.008 |
Hexadecaenoic | 0.003 |
Stearic | 0.022 |
Oleic | 0.035 |
Vaccenic | 0.014 |
Linoleic | 0.005 |
Linolenic | 0.003 |
Stearidonic | 0.012 |
Arachidic | 0.041 |
Eicosenoic | 0.078 |
Gondonic | 0.011 |
Arachidonic | 0.030 |
Eicosatetraenoic | 0.032 |
Eicosapentaenoic | 0.518 |
Behenic | 0.041 |
Erucic | 0.078 |
Adrenic | 0.013 |
Docosapentaenoic | 0.025 |
Docosapentaenoic | 0.192 |
Lignoceric | 0.012 |
Docosahexaenoic | 1.149 |
Nervonic | 0.061 |
Total ω3 | 1.906 |
Total ω6 | 0.060 |
Total ω9 | 0.175 |
SFAs | 0.129 |
MUFAs | 0.286 |
PUFAs | 1.949 |
Age-Matched Comparisons 1 | Alox5 | Alox8 | Alox15 | Elovl4 |
---|---|---|---|---|
C-rd10 P13 | 0.0018 | 0.0013 | 0.1510 | 0.215 |
C-rd10 P15 | 0.0006 | 0.6846 | 0.0003 | 0.0242 |
C-rd10 P18 | 0.0315 | 0.0677 | 0.0001 | 0.0163 |
C-rd10 P23 | <0.0001 | 0.0203 | <0.0001 | <0.0001 |
C-rd10 P30 | 0.208 | <0.0001 | 0.4610 | <0.0001 |
C-rd10 P44 | 0.9214 | <0.0001 | 0.0003 | <0.0001 |
C-rd10 P60 | 0.1512 | 0.3495 | 0.0003 | <0.0001 |
Iba1 + cells (%) | ONL Mean (SEM) | OPL Mean (SEM) | INL Mean (SEM) | IPL Mean (SEM) | GCL Mean (SEM) |
---|---|---|---|---|---|
C | 0.3 (0.3) | 25.5 (3.9) | 5.3 (3.8) | 44.3 (2.4) | 24.5 (2.1) |
rd10 | 30.7 (2.8) | 18.9 (1.2) | 10.6 (1.9) | 18.8 (1.8) | 21.1 (1.0) |
rd10 + EFA | 16.0 (3.5) | 26.7 (1.0) | 4.2 (1.5) | 26.0 (1.5) | 27.3 (3.8) |
Marker | C Mean (SEM) | rd10 Mean (SEM) | rd10 + EFA Mean (SEM) |
---|---|---|---|
SOD activity | 1.93 (0.17) | 2.05 (0.2) | 1.67 (0.19) |
CAT activity | 5.18 (0.53) | 7.22 (0.71) | 7.73 (0.43) * |
TBARS | 0.35 (0.07) | 1.14 (0.19) *** | 0.38 (0.13) # |
CAR | 3.78 (0.42) | 6.06 (0.29) *** | 3.55 (0.50) ## |
Phenotypes | Stimuli | Surface Markers | Intracellular Markers | Functions |
---|---|---|---|---|
M1 | IFNγ, LPS, GM-CSF, TNFα | CXCL9, CD86, CD80, CD16/32 | IL6, TNFα, iNOS, IL12high/IL10low | Pro-inflammatory |
M2a | IL4, IL13 | CD206, IL1-R | CCL17, IL10, ARG1 | Anti-inflammatory, repair and resolution |
M2b | LPS+ immune complex, ILβ+ immune complex | CD86, CD80 | TNFα, IL6, iNOS, COX2, CCL1, IL10high/IL12low | Regulatory T cell recruitment |
M2c | IL10, glucocorticoids | IL4R, CD206, CD163 | IL10, TGFβ, Arg1 | Immunoregulation, phagocytosis, tissue remodeling |
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Olivares-González, L.; Velasco, S.; Gallego, I.; Esteban-Medina, M.; Puras, G.; Loucera, C.; Martínez-Romero, A.; Peña-Chilet, M.; Pedraz, J.L.; Rodrigo, R. An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in rd10 Mice. Antioxidants 2023, 12, 98. https://doi.org/10.3390/antiox12010098
Olivares-González L, Velasco S, Gallego I, Esteban-Medina M, Puras G, Loucera C, Martínez-Romero A, Peña-Chilet M, Pedraz JL, Rodrigo R. An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in rd10 Mice. Antioxidants. 2023; 12(1):98. https://doi.org/10.3390/antiox12010098
Chicago/Turabian StyleOlivares-González, Lorena, Sheyla Velasco, Idoia Gallego, Marina Esteban-Medina, Gustavo Puras, Carlos Loucera, Alicia Martínez-Romero, María Peña-Chilet, José Luis Pedraz, and Regina Rodrigo. 2023. "An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in rd10 Mice" Antioxidants 12, no. 1: 98. https://doi.org/10.3390/antiox12010098