Caveolin-1 increases proinflammatory chemoattractants and blood-retinal barrier breakdown but decreases leukocyte recruitment in inflammation.
Caveolin-1 increases proinflammatory chemoattractants and blood-retinal barrier breakdown but decreases leukocyte recruitment in inflammation.
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Caveolin-1 会增加促炎化学引诱物和血-视网膜屏障的破坏，但会减少炎症中白细胞的募集。
DOI：
10.1167/iovs.14-14613
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发表时间：
2014
影响因子：
4.4
通讯作者：
Elliott,MichaelH
中科院分区：
文献类型：
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作者：
Li,Xiaoman;Gu,Xiaowu;Boyce,TimothyM;Zheng,Min;Reagan,AlainaM;Qi,Hui;Mandal,Nawajes;Cohen,AlexW;Callegan,MichelleC;Carr,DanielJJ;Elliott,MichaelH
目的：小窝蛋白-1（Caveolin-1，Cav-1）是小窝的标志性蛋白，调节炎症反应和先天免疫。然而，Cav-1在视网膜炎症中的作用尚未得到严格的测试。在这项研究中，我们检查了Cav-1消融对视网膜对炎症的敏感性的影响。通过玻璃体内注射脂多糖（LPS）攻击Cav-1敲除（KO）小鼠，并通过流式细胞术和免疫组织化学评估炎性细胞募集。用FITC标记的伴刀豆球蛋白A（FITC-ConA）灌注后，在视网膜平板中评估白细胞停滞。通过多重免疫测定法测量化学引诱剂。通过FITC-葡聚糖渗透性测定定量评估血视网膜屏障（BRB）的破坏。通过CD 45免疫组化法测定视网膜平台的血管外免疫细胞与总免疫细胞的比例。炎症激发导致Cav-1 KO视网膜中促炎细胞因子（单核细胞趋化蛋白-1 [MCP-1/CCL 2]、CXCL 1/KC、IL-6和IL-1β）反应显著减弱，以及炎性BRB分解减少。与对照组相比，Cav-1缺陷导致免疫细胞募集显著增加，白细胞停滞增加。在Cav-1 KO和野生型（WT）视网膜中发现血管外白细胞/总白细胞的相似比例，表明Cav-1缺陷型白细胞与WT小鼠的白细胞一样有能力外渗。我们发现，与对照组相比，在幼稚（未用LPS攻击）Cav-1 KO小鼠中循环免疫细胞的水平增加。Caveolin-1通过不同的机制矛盾地调节炎症信号和白细胞浸润。我们推测Cav-1表达可能增强炎症信号，同时支持BRB的物理特性。
Purpose.: Caveolin-1 (Cav-1), the signature protein of caveolae, modulates inflammatory responses, and innate immunity. However, Cav-1′ s role in retinal inflammation has not been rigorously tested. In this study, we examined the effect of Cav-1 ablation on the sensitivity of the retina to inflammation.Methods.: Cav-1 knockout (KO) mice were challenged by intravitreal injection of lipopolysaccharide (LPS) and inflammatory cell recruitment was assessed by flow cytometry and immunohistochemistry. Leukostasis was assessed in retinal flatmounts after perfusion with FITC-labeled Concanavalin A (FITC-ConA). Chemoattractants were measured by multiplex immunoassays. Blood–retinal barrier (BRB) breakdown was assessed quantitatively by a FITC-dextran permeability assay. The ratio of extravascular to total immune cells was determined by CD45 immunohistochemistry of retinal flatmounts.Results.: Inflammatory challenge resulted in significant blunting of proinflammatory cytokine (monocyte chemoattractant protein-1 [MCP-1/CCL2], CXCL1/KC, IL-6, and IL-1β) responses as well as reduced inflammatory BRB breakdown in Cav-1 KO retinas. Paradoxically, Cav-1 deficiency resulted in significantly increased recruitment of immune cells compared with controls as well as increased leukostasis. A similar ratio of extravascular/total leukocytes were found in Cav-1 KO and wild-type (WT) retinas suggesting that Cav-1 deficient leukocytes were as competent to extravasate as those from WT mice. We found increased levels of circulating immune cells in naïve (not challenged with LPS) Cav-1 KO mice compared with controls.Conclusions.: Caveolin-1 paradoxically modulates inflammatory signaling and leukocyte infiltration through distinct mechanisms. We hypothesize that Cav-1 expression may enhance inflammatory signaling while at the same time supporting the physical properties of the BRB.