Dysregulation of TIM-3–Galectin-9 Pathway in the Cystic Fibrosis Airways
Dysregulation of TIM-3–Galectin-9 Pathway in the Cystic Fibrosis Airways
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DOI：
10.4049/jimmunol.1003187
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发表时间：
2011-03
期刊：
影响因子：
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通讯作者：
I. Vega-Carrascal;E. Reeves;T. Niki;T. Arikawa;P. McNally;S. O’Neill;M. Hirashima;N. McElvaney
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文献类型：
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作者：
I. Vega-Carrascal;E. Reeves;T. Niki;T. Arikawa;P. McNally;S. O’Neill;M. Hirashima;N. McElvaney
T细胞免疫球蛋白和粘蛋白结构域包含分子(TIMs)已成为纠正多种自身免疫和慢性炎症条件下异常免疫功能的有希望的治疗靶点。据报道，促炎细胞因子失衡和以中性粒细胞为主的炎症反应是囊性纤维化发病的主要原因。然而，TIM受体在CF中的作用尚未被研究。在本研究中，我们发现TIM-3在人肺间质纤维上呈结构性过表达，提示纤维跨膜电导调节因子(CFTR)的功能与TIM-3的表达之间存在联系。用CFTR抑制剂-172阻断CFTR功能可诱导正常支气管上皮细胞TIM-3及其配体Galectin-9表达上调。我们还证实了TIM-3在支气管上皮细胞中是一种功能性受体，生理浓度的Galectin-9诱导TIM-3磷酸化，从而增加IL-8的产生。此外，我们还证明了TIM-3和Galectin-9在肺组织中都经历了快速的蛋白降解，这主要是由于中性粒细胞弹性蛋白酶和蛋白酶-3的活性所致。我们的结果提示了一种新的固有缺陷，可能与CF气道中性粒细胞主导的免疫反应有关。
The T-cell Ig and mucin domain-containing molecules (TIMs) have emerged as promising therapeutic targets to correct abnormal immune function in several autoimmune and chronic inflammatory conditions. It has been reported that proinflammatory cytokine dysregulation and neutrophil-dominated inflammation are the main causes of morbidity in cystic fibrosis (CF). However, the role of TIM receptors in CF has not been investigated. In this study, we demonstrated that TIM-3 is constitutively overexpressed in the human CF airway, suggesting a link between CF transmembrane conductance regulator (CFTR) function and TIM-3 expression. Blockade of CFTR function with the CFTR inhibitor-172 induced an upregulation of TIM-3 and its ligand galectin-9 in normal bronchial epithelial cells. We also established that TIM-3 serves as a functional receptor in bronchial epithelial cells, and physiologically relevant concentrations of galectin-9 induced TIM-3 phosphorylation, resulting in increased IL-8 production. In addition, we have demonstrated that both TIM-3 and galectin-9 undergo rapid proteolytic degradation in the CF lung, primarily because of neutrophil elastase and proteinase-3 activity. Our results suggest a novel intrinsic defect that may contribute to the neutrophil-dominated immune response in the CF airways.