Macular edema (ME) is a leading cause of visual impairment, and is associated with retinal barrier dysfunction and the consequent accumulation of extracellular fluid within the central retina.
1,2 Although a comprehensive understanding of its underlying pathophysiology remains elusive, vascular endothelial growth factor (VEGF) is known to have a key role in ME associated with retinal ischemia and inflammation, and intraocular injections of anti-VEGF agents are now standard treatment for diabetic macula edema (DME) and retinal vein occlusion (RVO), with ranibizumab (Lucentis; Genentech, South San Francisco, CA) and aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, NY) being approved by the United States Food and Drug Administration and European Medicines Agency for these indications. Furthermore, bevacizumab (Avastin; Roche, Basel, Switzerland) also is used off-label for treating retinal diseases, including the orphan indication of uveitic ME (UME).
3–5 However, despite the visual benefits anti-VEGF treatments have achieved, they fail to resolve ME in >20% of patients with DME
6 and in >40% of patients with RVO and uveitis/UME,
7,8 suggesting that there also are important alternative mediators of retinal barrier dysfunction. Principal among these is the cytokine interleukin-6 (IL-6) as its intraocular concentration correlates with the severity of ME in a diverse range of retinal pathologies, including diabetic retinopathy, DME, RVO, and uveitis.
9,10–12 The impact of IL-6 on vascular permeability already has been studied in a variety of nonocular tissues and cancer.
13,14 Our group and others have reported previously that in patients with refractory UME, systemic inhibition of IL-6 signaling with the IL-6 receptor (IL-6R) monoclonal antibody tocilizumab (TCZ – Actemra; Hoffmann-La Roche Ltd, Basel, Switzerland) was beneficial at 6, 12, and 24 months,
15–17 in particular with regard to achieving a reduction in central retinal thickness where other therapies had failed. However, the direct effect of IL-6 on the human blood retinal barrier (BRB) is yet to be fully elucidated. Therefore, we designed the present laboratory study to model the inner BRB using human retinal microvascular endothelial cells (HRMEC) and the outer BRB using human retinal pigment epithelial (ARPE-19) cells, with the goal of interrogating the effects of IL-6 and IL-6R blockade on in vitro measures of BRB integrity.