| First Author | Portillo JC | Year | 2017 |
| Journal | Diabetes | Volume | 66 |
| Issue | 2 | Pages | 483-493 |
| PubMed ID | 27474370 | Mgi Jnum | J:247095 |
| Mgi Id | MGI:5923728 | Doi | 10.2337/db16-0051 |
| Citation | Portillo JC, et al. (2017) CD40 in Retinal Muller Cells Induces P2X7-Dependent Cytokine Expression in Macrophages/Microglia in Diabetic Mice and Development of Early Experimental Diabetic Retinopathy. Diabetes 66(2):483-493 |
| abstractText | Muller 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 Muller cells, we identified a mechanism by which Muller cells trigger proinflammatory cytokine expression in myeloid cells. During diabetes, mice with CD40 expressed in Muller cells upregulated retinal tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), intracellular adhesion molecule 1 (ICAM-1), and nitric oxide synthase (NOS2), developed leukostasis and capillary degeneration. However, CD40 did not cause TNF-alpha or IL-1beta secretion in Muller cells. TNF-alpha was not detected in Muller cells from diabetic mice with CD40+ Muller cells. Rather, TNF-alpha was upregulated in macrophages/microglia. CD40 ligation in Muller cells triggered phospholipase C-dependent ATP release that caused P2X7-dependent production of TNF-alpha and IL-1beta by macrophages. P2X7-/- mice and mice treated with a P2X7 inhibitor were protected from diabetes-induced TNF-alpha, IL-1beta, ICAM-1, and NOS2 upregulation. Our studies indicate that CD40 in Muller cells is sufficient to upregulate retinal inflammatory markers and appears to promote experimental diabetic retinopathy and that Muller cells orchestrate inflammatory responses in myeloid cells through a CD40-ATP-P2X7 pathway. |
