NPD1-mediated stereoselective regulation of BIRC3 expression through cREL is decisive for neural cell survival

Abstract

Neuroprotectin D1 (NPD1), a docosahexaenoic acid (DHA)-derived mediator, induces cell survival in uncompensated oxidative stress (OS), neurodegenerations or ischemic stroke. The molecular principles underlying this protection remain unresolved. We report here that, in retinal pigment epithelial cells, NPD1 induces nuclear translocation and cREL synthesis that, in turn, mediates BIRC3 transcription. NPD1 activates NF-κB by an alternate route to canonical signaling, so the opposing effects of TNFR1 and NPD1 on BIRC3 expression are not due to interaction/s between NF-κB pathways. RelB expression follows a similar pattern as BIRC3, indicating that NPD1 also is required to activate cREL-mediated RelB expression. These results suggest that cREL, which follows a periodic pattern augmented by the lipid mediator, regulates a cluster of NPD1-dependent genes after cREL nuclear translocation. BIRC3 silencing prevents NPD1 induction of survival against OS. Moreover, brain NPD1 biosynthesis and selective neuronal BIRC3 abundance are increased by DHA after experimental ischemic stroke followed by remarkable neurological recovery. Thus, NPD1 bioactivity governs key counter-regulatory gene transcription decisive for retinal and brain neural cell integrity when confronted with potential disruptions of homeostasis.

Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aβ42 Phagocytosis

“…This is in line with a study on murine and human macrophages in which pre-treatment with LXA 4 diminished STS-induced apoptosis by promoting the PI3K/Akt and ERK/Nrf-2 pathway, and preserving mitochondrial function and integrity [55]. Reduction in oxidative stress has been shown to be involved in the protective effect of PD1 in in vitro models of neurodegeneration [56,57]. PDX, used in the present study, is an endogenous isomer of PD1, and differs from PD1 with regard to its biosynthetic route, chemical structure and potency [58].…”

Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury

“…Yet most SPM actions have been linked to their established antiinflammatory and proresolving activities. To our knowledge, only the structurally distinct DHA derivative, NPD1, has been linked directly to neuroprotective actions (45,46). The lipoxins were the first identified and remain the only AA-derived SPMs.…”

ER stress and impaired autophagy flux in neuronal degeneration and brain injury

“…Another DHA derivative involved in signal cascade that has been well studied is neuroprotectin D1 (NPD1). NPD1 induces cREL transcription and nuclear translocation, which promotes BIRC3 transcription for cell survival against oxidative stress (Calandria et al, 2015). In particular, NPD1 prevents oxidative stress induced cell death by up-regulating the anti-apoptotic proteins Bcl-2 and Bcl-xL while inhibiting pro-apoptotic Bax, Bad, and caspase-3 (Bazan, 2005).…”