Integrin αDβ2 is dynamically expressed by inflamed macrophages and alters the natural history of lethal systemic infections
Integrin αDβ2 is dynamically expressed by inflamed macrophages and alters the natural history of lethal systemic infections
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DOI：
10.4049/jimmunol.180.1.590
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发表时间：
2008-01-01
影响因子：
4.4
通讯作者：
Zimmerman, Guy A.
中科院分区：
文献类型：
--
作者：
Miyazaki, Yasunari;Bunting, Michaeline;Zimmerman, Guy A.
白细胞整合素在宿主防御和炎性组织损伤中起重要作用。我们发现，整合素α(D)β(2)是这个家族中一个新的但基本上没有特征的成员，它仅限于巨噬细胞亚群和一小部分循环中的白细胞；在没有炎症刺激的野生型小鼠中，整合素α(D)β(2)在细胞因子诱导的巨噬细胞体外分化过程中以受调控的方式表达。α(D)β(2)高度表达在脾红髓巨噬细胞上，调节其与局部靶点的黏附，识别关键的功能活动。为了应对伯氏疟原虫(一种模拟全身感染和炎性损伤的疟疾病原体)的挑战，新的α(+)(D)巨噬细胞群体在脾和肝脏中进化。出乎意料的是，在30天的观察期内，阿尔法(D)的定向缺失赋予了伯氏肺孢子虫感染的生存优势。机械学研究表明，在这些时间点，α(-/-)(D)动物存活率的增加不是由于贫血或寄生虫血症的程度不同，也不是因为脾显微解剖的变化，每一种变化都是伯氏疟原虫感染自然历史的关键变量，并表明炎性细胞因子模式的改变可能导致死亡率的差异。与疟疾挑战的结果相反，在沙门氏菌败血症模型中，α(-/-)(D)动物的死亡被加速，表明α(D)β(2)在全身感染中的不同角色而不是刻板印象。这些研究发现，在宿主防御和损伤中，α(D)β(2)和表达α(D)β(2)的巨噬细胞具有先前未被识别的独特活性。
The leukocyte integrins have critical roles in host defense and inflammatory tissue injury. We found that integrin alpha(D)beta(2), a novel but largely uncharacterized member of this family, is restricted to subsets of macrophages and a small population of circulating leukocytes; in wild-type mice in the absence of inflammatory challenge and is expressed in regulated fashion during cytokine-induced macrophage differentiation in vitro. alpha(D)beta(2) is highly displayed on splenic red pulp macrophages and mediates their adhesion to local targets, identifying key functional activity. In response to challenge with Plasmodium berghei, a malarial pathogen that models systemic infection and inflammatory injury, new populations of alpha(+)(D) macrophages evolved in the spleen and liver. Unexpectedly, targeted deletion of alpha(D), conferred a survival advantage in P. berghei infection over a 30-day observation period. Mechanistic studies demonstrated that the increased survival of alpha(-/-)(D) animals at these time points is not attributed to differences in magnitude of anemia or parasitemia or to alterations in splenic microanatomy, each of which is a key variable in the natural history of P. berghei infection, and indicated that an altered pattern of inflammatory cytokines may contribute to the difference in mortality. In contrast to the outcome in malarial challenge, death of alpha(-/-)(D) animals was accelerated in a model of Salmonella sepsis, demonstrating differential rather than stereotyped roles for alpha(D)beta(2) in systemic infection. These studies identify previously unrecognized and unique activities of alpha(D)beta(2), and macrophages; that express it, in host defense and injury.