Non-Hematopoietic β-Arrestin1 Confers Protection Against Experimental Colitis.
Non-Hematopoietic β-Arrestin1 Confers Protection Against Experimental Colitis.
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DOI：
10.1002/jcp.25216
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发表时间：
2016-05
影响因子：
5.6
通讯作者：
Parameswaran N
中科院分区：
文献类型：
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作者：
Lee T;Lee E;Arrollo D;Lucas PC;Parameswaran N
β-Arrestins是一种多功能的支架蛋白，在各种类型的细胞中调节G蛋白偶联受体（GPCR）依赖性和非依赖性细胞信号传导途径。我们最近发现β-arrestin 1（β-arr 1）缺乏显著减弱葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎。由于DSS诱导的结肠炎部分依赖于肠上皮损伤，我们使用结肠上皮细胞系SW 480细胞检测了β-arr 1在肠上皮细胞（IEC）中的作用。令人惊讶的是，我们发现在SW 480细胞中敲低β-arr 1通过caspase-3依赖性过程增强上皮细胞死亡。为了了解β-arr 1在结肠炎发展中的体内相关性和潜在的细胞类型特异性作用，我们在造血或非造血区室中产生了β-arr 1缺陷的骨髓嵌合体。然后使重构的嵌合小鼠经受DSS诱导的结肠炎。与我们先前的发现相似，造血区室中的β-arr 1缺陷保护小鼠免受DSS诱导的结肠炎。然而，与β-arr 1在体外上皮细胞凋亡中的作用一致，非造血β-arr 1缺陷导致结肠炎表型恶化。为了进一步了解信号转导机制，我们检测了β-arr 1对TNF-α介导的NFκB和MAPK通路的影响。我们的研究结果表明，β-arr 1在调节TNF-α介导的IEC ERK、JNK和p38 MAPK通路中具有关键作用。总之，我们的研究结果表明，造血和非造血细胞中的β-arr 1依赖性信号传导差异调节结肠炎发病机制，并进一步证明上皮细胞中的β-arr 1抑制TNF-α诱导的细胞死亡途径。
β-Arrestins are multifunctional scaffolding proteins that modulate G protein-coupled receptor (GPCR)-dependent and -independent cell signaling pathways in various types of cells. We recently demonstrated that β-arrestin1 (β-arr1) deficiency strikingly attenuates dextran sodium sulfate (DSS)-induced colitis in mice. Since DSS-induced colitis is in part dependent on gut epithelial injury, we examined the role of β-arr1 in intestinal epithelial cells (IECs) using a colon epithelial cell line, SW480 cells. Surprisingly, we found that knockdown of β-arr1 in SW480 cells enhanced epithelial cell death via a caspase-3-dependent process. To understand the in vivo relevance and potential cell type-specific role of β-arr1 in colitis development, we generated bone marrow chimeras with β-arr1 deficiency in either the hematopoietic or non-hematopoietic compartment. Reconstituted chimeric mice were then subjected to DSS-induced colitis. Similar to our previous findings, β-arr1 deficiency in the hematopoietic compartment protected mice from DSS-induced colitis. However, consistent with the role of β-arr1 in epithelial apoptosis in vitro, non-hematopoietic β-arr1 deficiency led to an exacerbated colitis phenotype. To further understand signaling mechanisms, we examined the effect of β-arr1 on TNF-α-mediated NFκB and MAPK pathways. Our results demonstrate that β-arr1 has a critical role in modulating ERK, JNK and p38 MAPK pathways mediated by TNF-α in IECs. Together, our results show that β-arr1-dependent signaling in hematopoietic and non-hematopoietic cells differentially regulates colitis pathogenesis and further demonstrates that β-arr1 in epithelial cells inhibits TNF-α-induced cell death pathways.