Modulation of Retinal Muller Cells by Complement Receptor C5aR

PURPOSE. Muller cells, a major type of glial cell found in the eye, are postulated to play an important role in many retinal diseases, including diabetic retinopathy (DR). Complement is an integral part of innate immunity, and the activation of complement has been associated with retinal diseases. However, the role of complement in the regulation of Muller cell function remains unclear. We were trying to address these issues in this study. METHODS. Using primary human Muller cells and a spontaneously immortalized human Muller cell line, we examined the expression of complement receptor C5aR both at mRNA and protein levels. Regulation of C5aR expression on Muller cells by prostaglandin E2 and by hyperglycemia, both of which are integrally involved in DR, were studied. Significance of C5aR on Muller cells was also investigated by examining relevant cytokine productions and their impacts on retinal endothelial cell proliferation/permeability after ligating the receptor using its ligand, C5a. RESULTS. C5aR is constitutively expressed in human Muller cells. Prostaglandin E2 and hyperglycemia individually and synergistically upregulate C5aR expression in Muller cells. Signaling through C5aR on Muller cells upregulates production of IL-6 and VEGF, which promotes the proliferation of human retinal endothelial cells and increases their permeability. CONCLUSIONS. These results indicate that complement can regulate Muller cells through C5aR, which may contribute to the pathogenesis of retinal diseases, including DR.