The CD40-ATP-P2X7 Receptor Pathway: Cell to Cell Cross-Talk to Promote Inflammation and Programmed Cell Death of Endothelial Cells

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-P2X 7 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.

Cerebral sterile inflammation in neurodegenerative diseases

“…The extracellular release of ATP induces the expression of MMP9 and IL-1β in injured brain tissue [ 15 ]. These inflammatory molecules promote the disruption of BBB through the degradation of tight junction proteins and endothelial cell death [ 16 ]. BBB disruption promotes the infiltration of circulating immune cells in the injured brain.…”

Nucleotides-Induced Changes in the Mechanical Properties of Living Endothelial Cells and Astrocytes, Analyzed by Atomic Force Microscopy

“…Undoubtedly, these studies could be applied to other nucleotide receptors. Ionotropic P2X and metabotropic P2Y nucleotide receptors are involved in mechanotransduction in different tissues in physiological conditions or after injury or inflammatory processes [ 32 , 51 , 52 , 53 , 54 , 55 , 56 ].…”

Proteomic phenotyping of stimulated Müller cells uncovers profound pro-inflammatory signaling and antigen-presenting capacity

“…Furthermore, our proteomic analysis revealed significantly higher abundance of the costimulatory molecule CD40 in pRMG after stimulation with IFNγ. Intriguingly, CD40 has been shown to play a vital role in DR pathogenesis (123)(124)(125). A study with transgenic mice, which express CD40 only in Müller cells, demonstrated that the upregulation of CD40 in Müller cells under diabetic conditions is sufficient for thriving leukostasis and degeneration of capillaries, thus promoting retinal inflammation and neurodegeneration in streptozotocin induced DR (124).…”