S100A8/A9 Proteins Mediate Neutrophilic Inflammation and Lung Pathology during Tuberculosis
S100A8/A9 Proteins Mediate Neutrophilic Inflammation and Lung Pathology during Tuberculosis
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DOI：
10.1164/rccm.201304-0803oc
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发表时间：
2013-11-01
影响因子：
24.7
通讯作者：
Khader, Shabaana A.
中科院分区：
文献类型：
--
作者：
Gopal, Radha;Monin, Leticia;Khader, Shabaana A.
理论基础：肺结核的一个特征是肉芽肿的形成。目的：本研究的目的是确定活动性肺结核炎性肉芽肿形成的潜在免疫机制。方法：利用人类标本和结核分枝杆菌感染的实验模型，利用分子和免疫学技术，对结核病期间炎性肉芽肿形成的免疫介质进行了研究。测量和主要结果：我们证明在活动性肺结核患者和非人类灵长类结核分枝杆菌感染模型中，在活动性肺结核期间见到的炎性肺肉芽肿中，产生S100蛋白的中性粒细胞占主导地位。利用结核病的小鼠模型，我们证明了中性粒细胞聚集导致的加重的肺部炎症依赖于S100A8/A9蛋白。S100A8/A9蛋白通过诱导促炎趋化因子和细胞因子的产生，并影响白细胞的运输，促进中性粒细胞聚集。重要的是，血清S100A8/A9蛋白水平和中性粒细胞相关趋化因子，如角质形成细胞趋化因子，可以作为评估肺结核患者肺部炎症和疾病严重程度的潜在替代生物标志物。结论：S100A8/A9蛋白在介导中性粒细胞聚集和与结核病相关的炎症反应中发挥了重要的病理作用。因此，靶向特定分子，如S100A8/A9蛋白，有可能在不影响对结核病的保护性免疫的情况下减少肺组织损伤。
Rationale: A hallmark of pulmonary tuberculosis (TB) is the formation of granulomas. However, the immune factors that drive the formation of a protective granuloma during latent TB, and the factors that drive the formation of inflammatory granulomas during active TB, are not well defined.Objectives: The objective of this study was to identify the underlying immune mechanisms involved in formation of inflammatory granulomas seen during active TB.Methods: The immune mediators involved in inflammatory granuloma formation during TB were assessed using human samples and experimental models of Mycobacterium tuberculosis infection, using molecular and immunologic techniques.Measurements and Main Results: We demonstrate that in human patients with active TB and in nonhuman primate models of M. tuberculosis infection, neutrophils producing S100 proteins are dominant within the inflammatory lung granulomas seen during active TB. Using the mouse model of TB, we demonstrate that the exacerbated lung inflammation seen as a result of neutrophilic accumulation is dependent on S100A8/A9 proteins. S100A8/A9 proteins promote neutrophil accumulation by inducing production of proinflammatory chemokines and cytokines, and influencing leukocyte trafficking. Importantly, serum levels of S100A8/A9 proteins along with neutrophil-associated chemokines, such as keratinocyte chemoattractant, can be used as potential surrogate biomarkers to assess lung inflammation and disease severity in human TB.Conclusions: Our results thus show a major pathologic role for S100A8/A9 proteins in mediating neutrophil accumulation and inflammation associated with TB. Thus, targeting specific molecules, such as S100A8/A9 proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB.