Endoplasmic reticulum (ER) stress is widely implicated in various pathological conditions such as diabetes. Previously, we reported that enhanced ER stress contributes to inflammation and vascular damage in diabetic and ischemia-induced retinopathy. However, the exact role of the signaling pathways activated by ER stress in vascular inflammation remains poorly understood. In the present study, we investigated the role of X-box binding protein 1 Diabetic retinopathy is a major complication of diabetes characterized by progressive damage of retinal microvasculature, disturbed blood supply, and retinal neuronal degeneration (1-4). One important function of retinal vascular system is to form the inner blood-retinal barrier (BRB).2 The inner BRB, composed of tight junctions between endothelial cells, selectively transport blood content into the retina and thus play an important role in maintaining retinal homeostasis and normal visual activity (5). Breakdown of the BRB due to endothelial cell injury is an early pathological event in diabetic retinopathy (6 -9). Impaired endothelial barrier allows macromolecules (proteins and lipids) and fluid leaking from blood vessels into retinal tissues, resulting in diabetic macular edema, the most frequent cause of vision impairment in patients with diabetes.A growing body of evidence suggests that leukocyte adhesion to endothelial cells and stasis in retinal vasculature (leukostasis) plays a causal role in BRB breakdown (10, 11). Binding of leukocytes to adhesion molecules on the surface of endothelial cells is required for leukostasis (12). During diabetes, endothelial cells are activated and express high levels of adhesion molecules (12, 13). In patients with diabetic retinopathy, levels of soluble intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in the vitreous are drastically enhanced(14), accompanied by increased inflammatory cells, including neutrophils, macrophages, and CD4 ϩ and CD8 ϩ T lymphocytes, in retinal blood vessels (15). Genetic depletion of ICAM-1 or its ligand abolishes retinal leukostasis and protects vascular cells from diabetes-induced apoptosis and vascular leakage (12). Similarly, inhibition of VCAM-1 reduces leukocyte adhesion and rolling in micro-and macrocirculations (16,17), suggesting that increased expression of adhesion molecules in endothelial cells is critical for leukostasis-mediated vascular injury. Among many potent stimulators of adhesion molecules, TNF-␣ is a major proinflammatory cytokine induced by diabetes in the retinal vascular system (18). Exposure of retinal endothelial cells to TNF-␣ induces rapid activation of NF-B and increased expression of ICAM-1 in parallel with tight junction damage (7). Inhibition of TNF-␣ function reduces leukostasisassociated retinal vascular leakage (11)