cRel and Wnt5a/Frizzled 5 Receptor-Mediated Inflammatory Regulation Reveal Novel Neuroprotectin D1 Targets for Neuroprotection
| Autor: | Jorgelina M. Calandria, Khanh V. Do, Sayantani Kala-Bhattacharjee, Andre Obenaus, Ludmila Belayev, Nicolas G. Bazan |
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| Rok vydání: | 2023 |
| Předmět: |
Neurology & Neurosurgery
Docosahexaenoic Acids Neuroprotectin D1 Ischemia-reperfusion Neurosciences Cell Biology General Medicine Pharmacology and Pharmaceutical Sciences Inflammatory cytokines Frizzled Receptors Neuroprotection Wnt-5a Protein Ischemia–reperfusion Stroke Cellular and Molecular Neuroscience Retinal pigment epithelial cells Uncompensated oxidative stress Wnt5a promoter Non-conventional cytokine Humans Human RPE cells 2.1 Biological and endogenous factors Biochemistry and Cell Biology Aetiology Ischemic Stroke |
| Zdroj: | Cellular and molecular neurobiology, vol 43, iss 3 |
| Popis: | Abstract Wnt5a triggers inflammatory responses and damage via NFkB/p65 in retinal pigment epithelial (RPE) cells undergoing uncompensated oxidative stress (UOS) and in experimental ischemic stroke. We found that Wnt5a-Clathrin-mediated uptake leads to NFkB/p65 activation and that Wnt5a is secreted in an exosome-independent fashion. We uncovered that docosahexaenoic acid (DHA) and its derivative, Neuroprotectin D1 (NPD1), upregulate c-Rel expression that, as a result, blunts Wnt5a abundance by competing with NFkB/p65 on the Wnt5a promoter A. Wnt5a increases in ischemic stroke penumbra and blood, while DHA reduces Wnt5a abundance with concomitant neuroprotection. Peptide inhibitor of Wnt5a binding, Box5, is also neuroprotective. DHA-decreased Wnt5a expression is concurrent with a drop in NFkB-driven inflammatory cytokine expression, revealing mechanisms after stroke, as in RPE cells exposed to UOS. Limiting the Wnt5a activity via Box5 reduces stroke size, suggesting neuroprotection pertinent to onset and progression of retinal degenerations and stroke consequences. Graphical Abstract NPD1 disrupts Wnt5a feedback loop at two sites: (1) decreasing FZD5, thus Wnt5a internalization, and (2) by enhancing cREL activity, which competes with p65/NFkB downstream endocytosis. As a result, Wnt5a expression is reduced, and so is its inflammatory signaling in RPE cells and neurons in ischemic stroke. |
| Databáze: | OpenAIRE |
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