TPC2 promotes choroidal angiogenesis and inflammation in a mouse model of neovascular age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly and can be classified either as dry or as neovascular (or wet). Neovascular AMD is characterized by a strong immune response and the inadequate release of cytokines triggering angiogenesis and induction of photoreceptor death. The pathomechanisms of AMD are only partly understood. Here, we identify the endolysosomal two-pore cation channel TPC2 as a key factor of neovascularization and immune activation in the laser-induced choroidal neovascularization (CNV) mouse model of AMD. Block of TPC2 reduced retinal VEGFA and IL-1β levels and diminished neovascularization and immune activation. Mechanistically, TPC2 mediates cationic currents in endolysosomal organelles of immune cells and lack of TPC2 leads to reduced IL-1β levels in areas of choroidal neovascularization due to endolysosomal trapping. Taken together, our study identifies TPC2 as a promising novel therapeutic target for the treatment of AMD.

More than meets the eye: The role of microglia in healthy and diseased retina

“…Interestingly, the endolysosomal system can also be manipulated in order to alleviate wet AMD conditions. Indeed, our group has recently shown that interfering with two-pore channel 2 (TPC2) function on endolysosomes in a model of laser-induced AMD leads to reduced recruitment of retinal microglia/macrophages ( 288 ). Moreover, Tpc2 knockout determines a reduction in neovascularization via a decrease in both VEGF and IL-1β levels, the latter being a pro-inflammatory interleukin that has been already associated with photoreceptor degeneration and pathological neovascularization ( 288 – 290 ).…”

“…Indeed, our group has recently shown that interfering with two-pore channel 2 (TPC2) function on endolysosomes in a model of laser-induced AMD leads to reduced recruitment of retinal microglia/macrophages ( 288 ). Moreover, Tpc2 knockout determines a reduction in neovascularization via a decrease in both VEGF and IL-1β levels, the latter being a pro-inflammatory interleukin that has been already associated with photoreceptor degeneration and pathological neovascularization ( 288 – 290 ). Further studies are currently undergoing to better characterize the mechanisms linking TPC2 to the beneficial effects observed.…”

Two-pore channels: going with the flows

“…TPCs contribute to cardiovascular complications. In blood vessels, TPCs exacerbate hypoxia-induced hypertension [ 117 , 118 ] or macular degeneration [ 119 ]. In the heart, the NAADP/TPC axis mediates adrenaline-evoked ionotropy [ 33 ] via local Ca 2+ signals at MCSs [ 120 ], and TPC2-KO mice manifest cardiac arrhythmias [ 121 ].…”

Blood Transcriptome Analysis of Beef Cow with Different Parity Revealed Candidate Genes and Gene Networks Regulating the Postpartum Diseases

“…TPCN2 protects against diet-induced weight gain in a mild manner, and this protection is likely independent of glucose tolerance, insulin sensitivity, and fasting plasma and hepatic lipid levels [ 34 ]. The endolysosomal two-pore cation channel TPCN2 is a key factor in neovascularization and immune activation [ 35 ]. TPCN2 acts on autophagy progression and extracellular vesicle transport in cancer cells [ 36 ].…”