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CD40 in Retinal Müller Cells Induces P2X7-Dependent Cytokine Expression in Macrophages/Microglia in Diabetic Mice and Development of Early Experimental Diabetic Retinopathy.

CD40 in Retinal Müller Cells Induces P2X7-Dependent Cytokine Expression in Macrophages/Microglia in Diabetic Mice and Development of Early Experimental Diabetic Retinopathy.
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Portillo JC, Corcino YL, Miao Y, Tang J, Sheibani N, Kern TS, Dubyak GR, Subauste CS,


Portillo JC, Corcino YL, Miao Y, Tang J, Sheibani N, Kern TS, Dubyak GR, Subauste CS, (click to view)

Portillo JC, Corcino YL, Miao Y, Tang J, Sheibani N, Kern TS, Dubyak GR, Subauste CS,

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Diabetes 2016 7 29() pii

Abstract

Müller cells and macrophages/microglia are likely important for 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 Müller cells, we identified a mechanism by which Müller cells trigger pro-inflammatory cytokine expression in myeloid cells. During diabetes, mice with CD40 expressed in Müller cells upregulated Müller TNF-α, IL-1β, ICAM-1 and NOS2, developed leukostasis and capillary degeneration. However, CD40 did not cause TNF-α or IL-1β secretion in Müller cells. TNF-α was not detected in Müller cells from diabetic mice with CD40(+) Müller cells. Rather, TNF-α was upregulated in macrophages/microglia. CD40 ligation in Müller cells triggered phospholipase C-dependent ATP release that caused P2X7-dependent production of TNF-α and IL-1β by macrophages. P2X7(-/-) mice and mice treated with a P2X7 inhibitor were protected from diabetes-induced TFN-α, IL-1β, ICAM-1 and NOS2 upregulation. Our studies indicate that CD40 in Müller cells is sufficient to upregulate retinal inflammatory markers and appears to promote experimental diabetic retinopathy, and they indicate that Müller cells orchestrate inflammatory responses in myeloid cells through a CD40-ATP-P2X7 pathway.

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