Targeted P2X7/NLRP3 signaling pathway against inflammation, apoptosis, and pyroptosis of retinal endothelial cells in diabetic retinopathy

Abstract

Retinal endothelial cells (RECs) are the primary target cells for diabetes-induced vascular damage. The P2X7/NLRP3 pathway plays an essential role in amplifying inflammation via an ATP feedback loop, promoting the inflammatory response, pyroptosis, and apoptosis of RECs in the early stages of diabetic retinopathy induced by hyperglycemia and inflammation. 3TC, a type of nucleoside reverse transcriptase inhibitor, is effective against inflammation, as it can targeting formation of the P2X7 large pore formation. Hence, our aim was to evaluated the anti-inflammatory effects and potential mechanisms of action of 3TC in vitro in retinal microvascular endothelial cells treated with high-glucose (HG) and lipopolysaccharide (LPS), as well as in vivo in the retinas of C57BL/6J male mice with streptozotocin-induced diabetes. The expression of inflammasome-related proteins P2X7 and NLRP3, and apoptosis in the retinas of 3TC-treated diabetic mice were compared to those of untreated diabetic mice. Furthermore, the anti-inflammatory, anti-apoptotic, and anti-pyroptotic effects of 3TC were evaluated in vitro in cultured mice retinal endothelial cells. Co-application of HG and LPS significantly increased the secretion of IL-6, IL-1β, and TNF-α, and ATP levels, whereas 3TC decreased cell inflammation, apoptosis, and pyroptosis. Inhibition of P2X7R and NLRP3 inflammasome activation decreased NLRP3 inflammasome-mediated injury. 3TC prevented cytokine and ATP release following co-application of HG and LPS/BzATP. Our findings provide new insights regarding the mechanisms of action of 3TC in diabetic environment-induced retinal injury, including apoptosis and pyroptosis.

ROS-triggered endothelial cell death mechanisms: Focus on pyroptosis, parthanatos, and ferroptosis

“…Kong et al. found that targeting the P2X7/NLRP3 signaling pathway prevents retinal endothelial cell pyroptosis in diabetic retinopathy ( 139 ). Kasson et al.…”

P2X7R/NLRP3 signaling pathway-mediated pyroptosis and neuroinflammation contributed to cognitive impairment in a mouse model of migraine

“…The activation of P2X7R can promote the formation of NLRP3 inflammasome [ 16 , 17 ], which is an intracellular multimeric protein complex that initiates inflammatory response and cell death (pyroptosis and apoptosis) by activating its effector caspase-1 [ 18 – 20 ]. The active caspase-1 facilitates the production of proinflammatory cytokines IL-1β and IL-18 [ 21 – 23 ], and activates pyroptosis-related protein Gasdermin D (GSDMD) and apoptosis-related protein caspase-3 [ 24 – 26 ]. This may lead to gliosis, neuronal loss and white matter damage, consequently leading to cognitive impairment [ 27 ].…”

lncRNA ZFAS1 Positively Facilitates Endothelial Ferroptosis via miR-7-5p/ACSL4 Axis in Diabetic Retinopathy

“…Apoptosis is known to be a major contributor to endothelial cell death [ 11 , 12 ]. However, several studies have pointed out that apoptosis itself cannot explain all the endothelial loss processes, making exploring new forms of cell death urgently needed [ 13 – 15 ]. Ferroptosis is a newly identified nonapoptosis cell death, characterized by lethal accumulation of intracellular iron and iron-induced lipid reactive oxygen species (ROS) [ 16 , 17 ].…”