CD40 in Retinal Mueller Cells Induces P2X_7-Dependent Cytokine Expression in Macrophages/Microglia in Diabetic Mice and Development of Early Experimental Diabetic Retinopathy

摘要

Mueller cells and macrophages/microglia are likely important for the development of diabetic retinopathy; however, the interplay between these cells in this disease is not well understood. An inflammatory process is linked to the onset of experimental diabetic retinopathy. CD40 deficiency impairs this process and prevents diabetic retinopathy. Using mice with CD40 expression restricted to Mueller cells, we identified a mechanism by which Mueller cells trigger proinf lammatory cytokine expression in my-eloid cells. During diabetes, mice with CD40 expressed in Mueller cells upregulated retinal tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), intracellular adhesion molecule 1 (ICAM-1), and nitric oxide synthase (NOS2), developed leukostasis and capillary degeneration. However, CD40 did not cause TNF-α or IL-1 β secretion in Mueller cells. TNF-α was not detected in Mueller cells from diabetic mice with CD40~+ Mueller cells. Rather, TNF-α was upregulated in macrophages/microglia. CD40 ligation in Mueller cells triggered phospholipase C-dependent ATP release that caused P2X_7-dependent production of TNF-α and IL-1β by macrophages. P2X_7~(-1-) mice and mice treated with a P2X_7 inhibitor were protected from diabetes-induced TNF-α, IL-1β, ICAM-1, and NOS2 upregulation. Our studies indicate that CD40 in Mueller cells is sufficient to upregulate retinal inflammatory markers and appears to promote experimental diabetic retinopathy and that Mueller cells orchestrate inflammatory responses in mye-loid cells through a CD40-ATP-P2X_7 pathway.