The IL-13/IL-4Rα axis is involved in tuberculosis-associated pathology.
The IL-13/IL-4Rα axis is involved in tuberculosis-associated pathology.
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DOI：
10.1002/path.4399
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发表时间：
2014-11
影响因子：
7.3
通讯作者：
Hoelscher, Christoph
中科院分区：
文献类型：
--
作者：
Heitmann, Lisa;Dar, Mahin Abad;Schreiber, Tanja;Erdmann, Hanna;Behrends, Jochen;Mckenzie, Andrew N. J.;Brombacher, Frank;Ehlers, Stefan;Hoelscher, Christoph
人类结核病是全球主要的健康威胁，仍然是一项重大的医疗挑战。然而，控制原发性结核病后组织病理的机制仍然难以捉摸，部分原因是缺乏遗传或免疫上可处理的动物模型。在人类结核病中，与肺损伤相关的白细胞介素(IL)-4和IL-13表达的相对大幅增加表明，在对结核分枝杆菌（Mtb）的反应中，一种颠覆性T辅助（TH）2成分可能破坏保护性免疫，并有助于再激活和组织病理。到目前为止，IL-4/IL-13-IL-4受体-α (Rα)介导的机制是否真的会引起再激活和病理，还没有明确的证据。不幸的是，实验小鼠结核中几乎没有中央坏死性肉芽肿与TH2免疫反应诱导不良有关。因此，我们假设，在小鼠中，IL-13的产生增加可能导致类似于人类原发性结核的病理。在我们的研究中，il -13过表达小鼠的气溶胶结核分枝杆菌感染实际上导致肺中央坏死性肉芽肿，伴有多核巨细胞，缺氧边缘和会阴坏死的胶原胶囊，邻近区域富含脂质，含抗酸杆菌的泡沫巨噬细胞，因此与人类原发性结核后的病理非常相似。mtb感染的il -13过表达小鼠肉芽肿坏死（GN）与表达精氨酸酶-1的巨噬细胞的诱导相关。间接阻断内源性精氨酸酶抑制剂l-羟精氨酸在mmb感染的野生型小鼠中导致精氨酸酶的强烈表达，并导致类似的GN病理。总之，我们在这里介绍了一个实验结核模型，该模型显示了人类原发性结核后中央坏死性肉芽肿的许多特征，并证明了导致精氨酸酶-1表达的IL-13/ il - 4r α-依赖机制参与了结核相关组织病理。©2014作者。由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版的病理学杂志。
Human tuberculosis (TB) is a leading global health threat and still constitutes a major medical challenge. However, mechanisms governing tissue pathology during post-primary TB remain elusive, partly because genetically or immunologically tractable animal models are lacking. In human TB, the demonstration of a large relative increase in interleukin (IL)-4 and IL-13 expression, which correlates with lung damage, indicates that a subversive T helper (TH)2 component in the response to Mycobacterium tuberculosis (Mtb) may undermine protective immunity and contribute to reactivation and tissue pathology. Up to now, there has been no clear evidence regarding whether IL-4/IL-13-IL-4 receptor-α (Rα)-mediated mechanisms may in fact cause reactivation and pathology. Unfortunately, the virtual absence of centrally necrotizing granulomas in experimental murine TB is associated with a poor induction of a TH2 immune response. We therefore hypothesize that, in mice, an increased production of IL-13 may lead to a pathology similar to human post-primary TB. In our study, aerosol Mtb infection of IL-13-over-expressing mice in fact resulted in pulmonary centrally necrotizing granulomas with multinucleated giant cells, a hypoxic rim and a perinecrotic collagen capsule, with an adjacent zone of lipid-rich, acid-fast bacilli-containing foamy macrophages, thus strongly resembling the pathology in human post-primary TB. Granuloma necrosis (GN) in Mtb-infected IL-13-over-expressing mice was associated with the induction of arginase-1-expressing macrophages. Indirect blockade of the endogenous arginase inhibitor l-hydroxyarginine in Mtb-infected wild-type mice resulted in a strong arginase expression and precipitated a similar pathology of GN. Together, we here introduce an experimental TB model that displays many features of centrally necrotizing granulomas in human post-primary TB and demonstrate that IL-13/IL-4Rα-dependent mechanisms leading to arginase-1 expression are involved in TB-associated tissue pathology. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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影响因子：
3.2
作者：
Hunter, Robert L.;Jagannath, Chinnaswamy;Actor, Jeffrey K.
通讯作者：
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4.3
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3.2
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