Spleen Tyrosine Kinase Contributes to Müller Glial Expression of Proangiogenic Cytokines in Diabetes.
Spleen Tyrosine Kinase Contributes to Müller Glial Expression of Proangiogenic Cytokines in Diabetes.
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DOI：
10.1167/iovs.63.11.25
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发表时间：
2022-10-03
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
--
作者：
神经胶质细胞功能障碍发生在糖尿病视网膜病变进展的早期。为了应对糖尿病或缺氧，穆勒神经胶质细胞分泌细胞因子和生长因子，促进疾病的进展。这项研究旨在研究1型糖尿病和前/2型糖尿病激活的Müler神经胶质细胞中常见的信号通路。通过RNA测序分析，比较了链脲佐菌素(STZ)和高脂高蔗糖(HFHS)饮食对Müler细胞mRNAs核糖体结合的影响。将人MIO-M1 Müler细胞暴露于高血糖或低氧培养条件下。用基因操作和药物抑制来询问信号通路。在STZ糖尿病小鼠和高脂饲料喂养的小鼠中，编码髓样细胞2触发受体(TREM2)、DNAX激活蛋白12 kDa(DAP12)和集落刺激因子1受体(CSF1R)的mRNAs与Müller胶质细胞分离的核糖体的关联性均上调。TREM2/DAP12受体-接头复合体与CSF1R协同激活脾酪氨酸激酶(SYK)。在糖尿病小鼠的视网膜和暴露于高血糖或低氧培养条件下的人Mio-M1 Müler细胞培养中，SYK的激活被增强。DAP12基因敲除降低了暴露在高血糖或低氧条件下的Müler细胞中SYK的自磷酸化。SYK抑制或DAP12基因敲除可抑制缺氧诱导的转录因子缺氧诱导因子1⍺(HIF1⍺)的表达，以及血管内皮生长因子和血管生成素样4的表达。这些结果支持通过SYK介导的TREM2/DAP12受体-适配器复合体信号转导促进HIF1α的稳定，增加Müller胶质细胞血管生成细胞因子的产生。
Neuroglial dysfunction occurs early in the progression of diabetic retinopathy. In response to diabetes or hypoxia, Müller glia secrete cytokines and growth factors that contribute to disease progression. This study was designed to examine common signaling pathways activated in Müller glia by both type 1 and pre-/type 2 diabetes. RiboTag (Pdgfra-cre;HA-Rpl22) mice were used to compare the impact of streptozotocin (STZ) and a high-fat, high-sucrose (HFHS) diet on ribosome association of mRNAs in Müller glia by RNA sequencing analysis. Human MIO-M1 Müller cells were exposed to either hyperglycemic or hypoxic culture conditions. Genetic manipulation and pharmacologic inhibition were used to interrogate signaling pathways. Association of mRNAs encoding triggering receptor expressed on myeloid cells 2 (TREM2), DNAX-activating protein 12 kDa (DAP12), and colony stimulating factor 1 receptor (CSF1R) with ribosomes isolated from Müller glia was upregulated in both STZ diabetic mice and mice fed an HFHS diet. The TREM2/DAP12 receptor-adaptor complex signals in coordination with CSF1R to activate spleen tyrosine kinase (SYK). SYK activation was enhanced in the retina of diabetic mice and in human MIO-M1 Müller cell cultures exposed to hyperglycemic or hypoxic culture conditions. DAP12 knockdown reduced SYK autophosphorylation in Müller cells exposed to hyperglycemic or hypoxic conditions. SYK inhibition or DAP12 knockdown suppressed hypoxia-induced expression of the transcription factor hypoxia-inducible factor 1⍺ (HIF1⍺), as well as expression of vascular endothelial growth factor and angiopoietin-like 4. The findings support TREM2/DAP12 receptor-adaptor complex signaling via SYK to promote HIF1α stabilization and increased angiogenic cytokine production by Müller glia.
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影响因子：
1.8
作者：
Hammer SS;Busik JV
通讯作者：
Busik JV
影响因子：
7.7
作者：
通讯作者：
--
影响因子：
64.5
作者：
Cowan CS;Renner M;De Gennaro M;Gross-Scherf B;Goldblum D;Hou Y;Munz M;Rodrigues TM;Krol J;Szikra T;Cuttat R;Waldt A;Papasaikas P;Diggelmann R;Patino-Alvarez CP;Galliker P;Spirig SE;Pavlinic D;Gerber-Hollbach N;Schuierer S;Srdanovic A;Balogh M;Panero R;Kusnyerik A;Szabo A;Stadler MB;Orgül S;Picelli S;Hasler PW;Hierlemann A;Scholl HPN;Roma G;Nigsch F;Roska B
通讯作者：
Roska B
影响因子：
4.8
作者：
Hubbi, Maimon E.;Hu, Hongxia;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
影响因子：
8.2
作者：
Lin M;Chen Y;Jin J;Hu Y;Zhou KK;Zhu M;Le YZ;Ge J;Johnson RS;Ma JX
通讯作者：
Ma JX