Neutrophils and the S100A9 protein critically regulate granuloma formation.
Neutrophils and the S100A9 protein critically regulate granuloma formation.
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DOI：
10.1182/bloodadvances.2016000497
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发表时间：
2016-12
期刊：
影响因子：
7.5
通讯作者：
Y. Yoshioka;T. Mizutani;S. Mizuta;A. Miyamoto;S. Murata;Toshiaki Ano;H. Ichise;D. Morita;Hiroyuki Yamada;Y. Hoshino;T. Tsuruyama;M. Sugita
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文献类型：
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作者：
Y. Yoshioka;T. Mizutani;S. Mizuta;A. Miyamoto;S. Murata;Toshiaki Ano;H. Ichise;D. Morita;Hiroyuki Yamada;Y. Hoshino;T. Tsuruyama;M. Sugita
巨噬细胞具有细胞转化为上皮样细胞的潜力，它们在组织中的同心积聚导致肉芽肿的发展。虽然上皮样细胞是肉芽肿的基本和主要组成部分，但也发现了其他类型的细胞，这可能有助于组织良好的肉芽肿的建立，正如在人类肉芽肿疾病中观察到的那样。我们在此证明中性粒细胞可能介导这些功能。利用豚鼠肺肉芽肿模型，获得一种对肉芽肿细胞具有独特反应性的大鼠单克隆抗体。这种抗体被命名为G213，与位于肉芽肿中心区域的中性粒细胞簇发生反应，生化分析鉴定出G213反应性抗原为S100A9，一种S100家族的钙结合蛋白，在中性粒细胞中大量表达。与S100A9的多方面功能（包括其在中性粒细胞外渗和巨噬细胞活化中的作用）一致，用特异性抑制剂tasquinimod阻断S100A9的功能，会损害具有中性粒细胞核心的有组织肉芽肿的形成。这些结果表明中性粒细胞和S100A9蛋白在肉芽肿形成中的关键作用。由于在人肉芽肿内也检测到S100A9+中性粒细胞，这些结果表明tasquinimod是一种新的抗癌候选药物，具有控制人肉芽肿疾病的潜力。
Macrophages have the potential to undergo cellular transformation into epithelioid cells, and their concentric accumulation in tissues results in the development of granulomas. Although epithelioid cells are an essential and dominant component of granulomas, other cell types have also been detected, which may contribute to the establishment of well-organized granulomas, as observed in human granulomatous diseases. We herein demonstrated that neutrophils may mediate these functions. By taking advantage of the guinea pig pulmonary granuloma model, we obtained a rat monoclonal antibody with unique reactivity to granuloma cells. This antibody, termed G213, reacted with clusters of neutrophils located in the central area of granulomas, and a biochemical analysis identified the G213-reactive antigen as S100A9, a calcium-binding protein of the S100 family, which was expressed abundantly in neutrophils. Consistent with the multifaceted functions attributed to S100A9, including its role in neutrophil extravasation and macrophage activation, the blockade of S100A9 functions with the specific inhibitor, tasquinimod, impaired the formation of organized granulomas with neutrophil cores. These results demonstrate the critical role of neutrophils and the S100A9 protein in granuloma formation. Because intragranuloma S100A9+ neutrophils were also detected in humans, these results indicate the potential of tasquinimod, a new anticancer drug candidate, for manipulating human granulomatous diseases.