Protective Role of β-arrestin2 in Colitis Through Modulation of T-cell Activation.
Protective Role of β-arrestin2 in Colitis Through Modulation of T-cell Activation.
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DOI：
10.1097/mib.0000000000000563
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发表时间：
2015-12
影响因子：
4.9
通讯作者：
Parameswaran N
中科院分区：
文献类型：
--
作者：
Sharma D;Malik A;Steury MD;Lucas PC;Parameswaran N
β-arrestin2 (β-arr2) 被鉴定为 GPCR 脱敏中的支架蛋白，是多种微生物败血症中炎症的负调节因子。在这项研究中，我们想要研究 β-arr2 在肠道炎症（持续微生物刺激的部位）中的作用。在缺乏 β-arr2 的情况下，即使在稳态条件下，小鼠也会表现出更大程度的粘膜炎症，这取决于细胞浸润和炎症介质的表达。此外，与野生型 (WT) 小鼠相比，β-arr2 缺陷小鼠更容易受到 DSS 诱导的结肠炎的影响，表现为体重减轻更大、疾病活动指数更高和结肠缩短。我们还表明，来自 β-arr2 KO 小鼠的 T 细胞在基础条件和结肠条件下均表现出激活状态的改变，这表明它们参与了疾病诱导。对 β-arr2 在内源性 T 细胞分化中的作用的进一步评估证实了其在 T 细胞极化中的重要性。利用结肠炎的 T 细胞转移模型，我们证明 T 细胞特异性-β-arr2 对于限制结肠炎炎症很重要；然而，它在并发的系统性消耗性疾病中发挥着矛盾的作用。总之，我们的研究强调了 β-arr2 在肠道炎症中的关键负调节作用，并证明了 T 细胞特异性 β-arr2 在全身消耗性疾病中的独特作用。
β-arrestin2 (β-arr2) identified as a scaffolding protein in GPCR desensitization, is a negative regulator of inflammation in polymicrobial sepsis. In this study we wanted to investigate the role of β-arr2 in intestinal inflammation, a site of persistent microbial stimulation. In the absence of β-arr2, mice exhibited greater extent of mucosal inflammation determined by cellular infiltration and expression of inflammatory mediators even under homeostatic conditions. Further, β-arr2 deficient mice were more susceptible to DSS induced colitis as demonstrated by greater body weight loss, higher disease activity index and shortened colon as compared to wild type (WT) mice. We also show that T cells from β-arr2 KO mice exhibit altered activation status under both basal and colitic conditions, implicating their involvement in disease induction. Further assessment of the role of β-arr2 in intrinsic T cell differentiation confirmed its importance in T cell polarization. Utilizing the T cell transfer model of colitis we demonstrate that T-cell specific-β-arr2 is important in limiting colitic inflammation; however it plays a paradoxical role in concurrent systemic wasting disease. Together, our study highlights a critical negative regulatory role of β-arr2 in intestinal inflammation and demonstrates a distinct role of T-cell-specific β-arr2 in systemic wasting disease.