Lipocalin 2 Plays an Important Role in Regulating Inflammation in Retinal Degeneration

Abstract

<p class="first" id="P1">It has become increasingly important to understand how retinal inflammation is regulated because inflammation plays a role in retinal degenerative diseases. Lipocalin 2 (LCN2), an acute stress response protein with multiple innate immune functions, is increased in <i>Abca4 ^−/−Rdh8 ^−/− </i> double knockout mice, an animal model for Stargardt disease and age-related macular degeneration (AMD). To examine roles of LCN2 in retinal inflammation and degeneration, <i>Lcn2 ^−/−Abca4 ^−/−Rdh8 ^−/− </i> triple knockout mice were generated. Exacerbated inflammation following light exposure was observed in <i>Lcn2 ^−/−Abca4 ^−/−Rdh8 ^−/− </i> mice as compared with <i>Abca4 ^−/−Rdh8 ^−/− </i> mice, with upregulation of pro-inflammatory genes and microglial activation. RNA array analyses revealed an increase in immune response molecules such as <i>Ccl8</i>, <i>Ccl2</i> and <i>Cxcl10</i>. To further probe a possible regulatory role for LCN2 in retinal inflammation, we examined the <i>in vitro</i> effects of LCN2 on NF-κB signaling in human retinal pigmented epithelial (RPE) cells differentiated from induced pluripotent stem cells (hiPS-RPE) derived from healthy donors. We found that LCN2 induced expression of antioxidant enzymes HMOX1 and SOD2 in these RPE cells and could inhibit the cytotoxic effects of H ₂O ₂ and lipopolysaccharide. Enzyme-linked Immunosorbent Assay revealed increased LCN2 levels in plasma of patients with Stargardt disease, retinitis pigmentosa and AMD as compared with healthy controls. Finally, overexpression of <i>LCN2</i> in RPE cells displayed protection from cell death. Overall these results suggest that LCN2 is involved in pro-survival responses during cell stress and plays an important role in regulating inflammation during retinal degeneration. </p>