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. 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.