Abstract
The transformation of microglia to a pro-inflammatory phenotype at the site of traumatic brain injury (TBI) drives the progression of secondary neurodegeneration and irreversible neurological impairment. Omega-3 polyunsaturated fatty acids (PUFA) have been shown to suppress this phenotype transformation, thereby reducing neuroinflammation following TBI, but the molecular mechanisms are unknown. We found that Omega-3 PUFA suppressed the expression of disintegrin metalloproteinase (ADAM17), the enzyme required to convert tumor necrosis factor-α (TNF-α) to the soluble form, thereby inhibiting the TNF-α/NF-κB pathway both in vitro and in a mouse model of TBI. Omega-3 PUFA also prevented the reactive transformation of microglia and promoted the secretion of microglial exosomes containing nerve growth factor (NGF), activating the neuroprotective NGF/TrkA pathway both in culture and TBI model mice. Moreover, Omega-3 PUFA suppressed the pro-apoptotic NGF/P75NTR pathway at the TBI site and reduced apoptotic neuronal death, brain edema, and disruption of the blood–brain barrier. Finally, Omega-3 PUFA preserved sensory and motor function as assessed by two broad-spectrum test batteries. The beneficial effects of Omega-3 PUFA were blocked by an ADAM17 promotor and by a NGF inhibitor, confirming the pathogenic function of ADAM17 and the central neuroprotective role of NGF. Collectively, these findings provide a strong experimental basis for Omega-3 PUFA as a potential clinical treatment for TBI.
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Data Availability
The datasets generated and/or analyzed for the present study are available from the corresponding author on reasonable request.
Abbreviations
- TBI:
-
Traumatic brain injury
- TNF-α:
-
Tumor necrosis factor-α
- ADAM17:
-
Extracellular a disintegrin metalloproteinase 17
- LPS:
-
Lipopolysaccharide
- IL:
-
Interleukin
- NF-κB:
-
Nuclear factor-κB
- NGF:
-
Nerve growth factor
- CCI:
-
Controlled cortical impact
- DHA:
-
Docosahexaenoic acid
- PMA:
-
Phorbol 12-myristate 13-acetate
- TNFR1:
-
Type 1 TNF receptor
- p-IκB:
-
Phosphorylated NF-κB inhibitory protein
- TEM:
-
Transmission electron microscopy
- P75NTR:
-
p75 neurotrophic factor receptor
- p-TrkA:
-
Phosphorylated tyrosine protein kinase A
- EB:
-
Evans blue
- Icam-1:
-
Intercellular adhesion molecule-1
- Hspa8:
-
Heat shock protein 8
- GUF-1:
-
GTPase homolog1
- FGG:
-
Fibrinogen gamma
- BBB:
-
Blood–brain barrier
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Acknowledgements
Sincere appreciation is also given to the teachers and our colleagues from the 900th Hospital, who participated in this study with great cooperation.
Funding
Joint Funds for the Innovation of Science and Technology, Fujian Province (Grant number: 2019Y9045); the 900th Hospital of Commanding Project and Special Treatment for Trauma (Grant number: 2022ZL03); Quanzhou City Science and Technology Program of China (Grant number:2022C030R); Joint Funds for the innovation of science and Technology, Fujian province (Grant number: 2020Y9033).
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LL: conceptualization (equal); formal analysis (equal); methodology (equal); writing—original draft (equal). SZ: formal analysis (equal); methodology (equal); software (equal). JL: data curation (equal); methodology (equal). DY: project administration (equal); formal analysis (equal). QH: project administration (equal); formal analysis (equal). ZW: methodology (equal); formal analysis (equal). XC: formal analysis (equal); methodology (equal); writing—review and editing (equal); funding acquisition (equal). SW: conceptualization (equal); funding acquisition (equal); project administration (equal); supervision (equal); writing—review and editing (equal).
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All protocols in this study were approved by the Committee on the Ethics of Animal Experiments of 900th Hospital of PLA (approval number: 2020-068), in compliance with the Guide for the Care and Use of Laboratory Animals published by the NIH.
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Lin, L., Zheng, S., Lai, J. et al. Omega-3 Polyunsaturated Fatty Acids Protect Neurological Function After Traumatic Brain Injury by Suppressing Microglial Transformation to the Proinflammatory Phenotype and Activating Exosomal NGF/TrkA Signaling. Mol Neurobiol 60, 5592–5606 (2023). https://doi.org/10.1007/s12035-023-03419-3
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DOI: https://doi.org/10.1007/s12035-023-03419-3