Abstract
Extracellular adenosine 5′-triphosphate (ATP) functions not only as a neurotransmitter but is also released by non-excitable cells and mediates cell–cell communication involving glia. In pathological conditions, extracellular ATP released by astrocytes may act as a “danger” signal that activates microglia and promotes neuroinflammation. This review summarizes in vitro and in vivo studies that identified CD40 as a novel trigger of ATP release and purinergic-induced inflammation. The use of transgenic mice with expression of CD40 restricted to retinal Müller glia and a model of diabetic retinopathy (a disease where the CD40 pathway is activated) established that CD40 induces release of ATP in Müller glia and triggers in microglia/macrophages purinergic receptor-dependent inflammatory responses that drive the development of retinopathy. The CD40-ATP-P2X7 pathway not only amplifies inflammation but also induces death of retinal endothelial cells, an event key to the development of capillary degeneration and retinal ischemia. Taken together, CD40 expressed in non-hematopoietic cells is sufficient to mediate inflammation and tissue pathology as well as cause death of retinal endothelial cells. This process likely contributes to development of degenerate capillaries, a hallmark of diabetic and ischemic retinopathies. Blockade of signaling pathways downstream of CD40 operative in non-hematopoietic cells may offer a novel means of treating diabetic and ischemic retinopathies.
Highlights
Glia orchestrate homeostasis in neural tissue through cell-to-cell interactions
The model that likely explains these findings is as follows: ischemia-induced activation of CD40 in retinal endothelial cells triggers ICAM-1 and KC/CXCL1 upregulation leading to recruitment of NOS2 and COX-2expressing leukocytes that would in turn promote neurovascular degeneration in the retina [5]
Studies in transgenic mice that expressed CD40 restricted to Müller glia demonstrated that, after induction of diabetes, the presence of CD40 in these cells was sufficient for upregulation of ICAM-1, NOS2, TNF-α, IL-1β, CCL2 mRNA levels as well as for development of leukostasis and capillary degeneration [7]
Summary
Glia orchestrate homeostasis in neural tissue through cell-to-cell interactions. Communication among glial subsets and communication between glia and other cells of the nervous system are important during the development of disorders with an inflammatory component. Immunohistochemistry and flow cytometry studies to assess protein expression revealed that CD40 is upregulated in retinal endothelial cells, Müller glia and microglia of diabetic mice [6].
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