Neurotrophins induce neuroprotective signaling in the retinal pigment epithelial cell by activating the synthesis of the anti-inflammatory and anti-apoptotic neuroprotectin D1

Abstract

The integrity of retinal pigment epithelial cells is critical for photoreceptor cell survival and vision. The essential omega-3 fatty acid, docosahexaenoic acid, attains its highest concentration in the human body in photoreceptors. Docosahexaenoic acid is the essential precursor of neuroprotectin D1 (NPD1). NPD1 acts against apoptosis mediated by A2E, a byproduct of phototransduction that becomes toxic when it accumulates in aging retinal pigment epithelial (RPE) cells and in some inherited retinal degenerations. Here we also describe that neurotrophins, mainly pigment epithelium-derived factor, induce NPD1 synthesis and its polarized apical secretion, suggesting paracrine and autocrine bioactivity of this lipid mediator. In addition, DHA elicits a concentration-dependent and selective potentiation of pigment epithelial-derived factor-stimulated NPD1 synthesis and release through the apical RPE cell surface. The bioactivity of signaling activated by PEDF and DHA demonstrates synergistic cytoprotection when cells were challenged with oxidative stress, resulting in concomitant NPD1 synthesis. Also, DHA and PEDF synergistically activate anti-apoptotic protein expression and decreased pro-apoptotic Bcl-2 protein expression and caspase 3 activation during oxidative stress. Thus, DHA-derived NPD1 protects against RPE cell damage mediated by aging/disease-induced A2E accumulation. Also, neurotrophins are regulators of NPD1 synthesis and of its polarized apical efflux from RPE cells. Therefore, NPD1 may elicit autocrine and paracrine bioactivity in cells located in the proximity of the interphotoreceptor matrix.

Figure 1

Illustration depicting NPD1 (neuroprotectin D1, 10S,17S-DHA) synthesis and bioactivity. Neurotrophins, mainly PEDF (pigment epithelium-derived factor) are NPD1 synthesis agonists in primary RPE cells in culture (Mukherjee et al., in press). Arrows indicate that PEDF may be secreted from the RPE cell or be derived from another cell. A putative PEDF receptor is indicated. A PLA₂ (phospholipase A₂) that mediates the cleavage of docosahexaenoyl chains from phospholipids located in RPE membranes and /or phagocytized photoreceptor membranes (POS, photoreceptor outer segment) is illustrated. Likely, a very specific pool of DHA-containing phospholipids is the precursor of docosanoids. A 15-lipoxygenase-1-like enzyme mediates NPD1 synthesis. Because PEDF has antiangiogenic properties, it is likely that NPD1-evoked synthesis by this neurotrophin may participate in this process. NPD1 potently downregulates IL-1β-induced COX-2 expression (Mukherjee et al., 2004) as well as other proinflammatory genes (Lukiw et al., 2005). NPD1 action on Bcl-2 proteins may be mediated by an autocrine route or by an intracellular action. NPD1 apically released may exert bioactivity on cells in the proximity of the interphotoreceptor matrix.