The immunocytes microglia in the central nervous system （CNS） were reported to play a crucial role in neurodegeneration. As a member of P2 receptors family, purinoceptor P2Y6 has attracted much attention recently. P...The immunocytes microglia in the central nervous system （CNS） were reported to play a crucial role in neurodegeneration. As a member of P2 receptors family, purinoceptor P2Y6 has attracted much attention recently. Previous studies showed that purinoceptor P2Y6 mainly contributed to microglia activation and their later phagocytosis in CNS, while in immune system, it participated in the secretion of interleukin （IL）-8 from monocytes and macrocytes. So there raises a question： whether purinoceptor P2Y6 also takes part in neuroinflammation？ Thus, this review mainly concerns about the properties and roles of purinoceptor P2Y6, including （1） structure of purinoceptor P2Y6; （2） distribution and properties of purinoceptor P2Y6; （3） relationships between purinoceptor P2Y6 and microglia; （4） relationships between purinoceptor P2Y6 and immunoinflammation. It＇s proposed that purinoceptor P2Y6 may play a role in neuroinflammation in CNS, although further research is still required.展开更多
OBJECTIVE Uridine adenosine tetraphosphate(Up4A),a dinucleotide,contains both purine and pyrimidine moieties,and exerts its vascular influence via activation of purinergic receptors.Here,we aimed to investigate the ef...OBJECTIVE Uridine adenosine tetraphosphate(Up4A),a dinucleotide,contains both purine and pyrimidine moieties,and exerts its vascular influence via activation of purinergic receptors.Here,we aimed to investigate the effects of Up4 A on angiogenesis and the putative purinergic receptors(PR)involved in this process.METHODS Tubule formation assay was performed in 3D matrix system.In this assay,human umbilical vein endothelial cells(HUVECs)were co-cultured with pericytes with various Up4 A doses(0,1,2.5,5,10 and 20μmol·L-1)in the absence and presence of P2Y6 R antagonist MRS2578(10μmol·L-1)for 5d.Expression profile of PR subtypes and angiogenic factors was assessed in HUVECs by q-PCR with and without P2Y6 R antagonist.RESULTS No difference in initial tubule formation was detected between Up4 A stimulation and control conditions at day 2.In contrast,a significant increase in vascular density in response to Up4 A was observed at day 5.Up4 A at a dose of 2.5and 5μmol·L-1 promoted total tubule length(by-1.89 fold and-2.23fold),number of tubules(by-1.71 fold and-1.89fold)as well as number of junctions(by-2.24 fold and-2.80fold),all of which were inhibited by MRS2578.Further increase in Up4 A dose to10 and 20μmol·L-1 did not induce an increase in these vascular parameters as compared to non-treated controls.Moreover,Up4 A increased mRNA level of P2YRs(P2Y2R,P2Y4 R and P2Y6R)but not P2XR(P2X4R and P2X7R)or P1R(A2AR and A2BR),while Up4 A upregulated VEGFA and ANGPT1 but not VEGFR2,ANGPT2,Tie1 and Tie2at mRNA level.Transcriptional upregulation of P2 YRs and angiogenic factors by Up4 A was inhibited by MRS2578.CONCLUSION Up4 A is functionally capable of promoting tubule formation in vitro co-culture system.This process is likely mediated by activation of pyrimidine-favored P2 YRs but not P2 XR or P1 Rs,and involves stimulation of well known angiogenic factors.展开更多
Purinergic signaling plays a causal role in the modulation of immune inflammatory response in the course of psoriasis,but its regulatory mechanism remains unclear.As a member of purinoceptors,P2Y_(6)R mainly distribut...Purinergic signaling plays a causal role in the modulation of immune inflammatory response in the course of psoriasis,but its regulatory mechanism remains unclear.As a member of purinoceptors,P2Y_(6)R mainly distributed in macrophages was significantly up-expressed in skin lesions from patients with psoriasis in the present study.Here,the severity of psoriasis was alleviated in imiquimod-treated mice with macrophages conditional knockout of P2Y_(6)R,while the cell-chat algorithm showed there was a correlation between macrophage P2Y_(6)R and Th1 cells mediated by IL-27.Mechanistically,P2Y_(6)R enhanced PLCβ/p-PKC/MAPK activation to induce IL-27 release dependently,which subsequently regulated the differentiation of Th1 cells,leading to erythematous and scaly plaques of psoriasis.Interestingly,we developed a novel P2Y_(6)R inhibitor FS-6,which bonds with the ARG266 side chain of P2Y_(6)R,exhibited remarkable anti-psoriasis effects targeting P2Y_(6)R.Our study provides insights into the role of P2Y_(6)R in the pathogenesis of psoriasis and suggests its potential as a target for the development of therapeutic interventions.A novel P2Y_(6)R inhibitor FS-6 could be developed as an anti-psoriasis drug candidate for the clinic.展开更多
基金supported by the Key Scientific Research Innovation Program of Shanghai Municipal Education Commission,China (No.082260)
文摘The immunocytes microglia in the central nervous system （CNS） were reported to play a crucial role in neurodegeneration. As a member of P2 receptors family, purinoceptor P2Y6 has attracted much attention recently. Previous studies showed that purinoceptor P2Y6 mainly contributed to microglia activation and their later phagocytosis in CNS, while in immune system, it participated in the secretion of interleukin （IL）-8 from monocytes and macrocytes. So there raises a question： whether purinoceptor P2Y6 also takes part in neuroinflammation？ Thus, this review mainly concerns about the properties and roles of purinoceptor P2Y6, including （1） structure of purinoceptor P2Y6; （2） distribution and properties of purinoceptor P2Y6; （3） relationships between purinoceptor P2Y6 and microglia; （4） relationships between purinoceptor P2Y6 and immunoinflammation. It＇s proposed that purinoceptor P2Y6 may play a role in neuroinflammation in CNS, although further research is still required.
文摘OBJECTIVE Uridine adenosine tetraphosphate(Up4A),a dinucleotide,contains both purine and pyrimidine moieties,and exerts its vascular influence via activation of purinergic receptors.Here,we aimed to investigate the effects of Up4 A on angiogenesis and the putative purinergic receptors(PR)involved in this process.METHODS Tubule formation assay was performed in 3D matrix system.In this assay,human umbilical vein endothelial cells(HUVECs)were co-cultured with pericytes with various Up4 A doses(0,1,2.5,5,10 and 20μmol·L-1)in the absence and presence of P2Y6 R antagonist MRS2578(10μmol·L-1)for 5d.Expression profile of PR subtypes and angiogenic factors was assessed in HUVECs by q-PCR with and without P2Y6 R antagonist.RESULTS No difference in initial tubule formation was detected between Up4 A stimulation and control conditions at day 2.In contrast,a significant increase in vascular density in response to Up4 A was observed at day 5.Up4 A at a dose of 2.5and 5μmol·L-1 promoted total tubule length(by-1.89 fold and-2.23fold),number of tubules(by-1.71 fold and-1.89fold)as well as number of junctions(by-2.24 fold and-2.80fold),all of which were inhibited by MRS2578.Further increase in Up4 A dose to10 and 20μmol·L-1 did not induce an increase in these vascular parameters as compared to non-treated controls.Moreover,Up4 A increased mRNA level of P2YRs(P2Y2R,P2Y4 R and P2Y6R)but not P2XR(P2X4R and P2X7R)or P1R(A2AR and A2BR),while Up4 A upregulated VEGFA and ANGPT1 but not VEGFR2,ANGPT2,Tie1 and Tie2at mRNA level.Transcriptional upregulation of P2 YRs and angiogenic factors by Up4 A was inhibited by MRS2578.CONCLUSION Up4 A is functionally capable of promoting tubule formation in vitro co-culture system.This process is likely mediated by activation of pyrimidine-favored P2 YRs but not P2 XR or P1 Rs,and involves stimulation of well known angiogenic factors.
基金supported by the funds from National Natural Science Foundation of China(No.82304506,No.82373887,No.82373725)the China Postdoctoral Science Foundation(2022M723513,China).
文摘Purinergic signaling plays a causal role in the modulation of immune inflammatory response in the course of psoriasis,but its regulatory mechanism remains unclear.As a member of purinoceptors,P2Y_(6)R mainly distributed in macrophages was significantly up-expressed in skin lesions from patients with psoriasis in the present study.Here,the severity of psoriasis was alleviated in imiquimod-treated mice with macrophages conditional knockout of P2Y_(6)R,while the cell-chat algorithm showed there was a correlation between macrophage P2Y_(6)R and Th1 cells mediated by IL-27.Mechanistically,P2Y_(6)R enhanced PLCβ/p-PKC/MAPK activation to induce IL-27 release dependently,which subsequently regulated the differentiation of Th1 cells,leading to erythematous and scaly plaques of psoriasis.Interestingly,we developed a novel P2Y_(6)R inhibitor FS-6,which bonds with the ARG266 side chain of P2Y_(6)R,exhibited remarkable anti-psoriasis effects targeting P2Y_(6)R.Our study provides insights into the role of P2Y_(6)R in the pathogenesis of psoriasis and suggests its potential as a target for the development of therapeutic interventions.A novel P2Y_(6)R inhibitor FS-6 could be developed as an anti-psoriasis drug candidate for the clinic.
