Systems biology predicts that fibrosis in tuberculous granulomas may arise through macrophage-to-myofibroblast transformation.
Systems biology predicts that fibrosis in tuberculous granulomas may arise through macrophage-to-myofibroblast transformation.
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DOI：
10.1371/journal.pcbi.1008520
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发表时间：
2020-12
影响因子：
4.3
通讯作者：
Kirschner DE
中科院分区：
文献类型：
--
作者：
Evans S;Butler JR;Mattila JT;Kirschner DE
结核分枝杆菌（Mtb）感染引起结核病（TB），这是一种以肉芽肿的发展为特征的疾病。肉芽肿由聚集在一起的激活的免疫细胞组成，以限制细菌生长和传播。结核病流行的控制受到长期药物治疗、抗生素耐药性和缺乏强有力的有效疫苗的限制。纤维化通常发生在治疗过程中，并与结核病的阳性和阴性疾病结局相关，但对肉芽肿中启动纤维化的过程知之甚少。经历纤维化的人类和非人类灵长类动物肉芽肿可以具有成纤维细胞样形态的纺锤形巨噬细胞，这表明巨噬细胞、成纤维细胞和肉芽肿纤维化之间的关系。由于人类病理学样本的有限可用性、人类TB涉及的时间尺度以及组织中成纤维细胞和骨髓细胞标记物之间的重叠，这种关系一直难以调查。为了更好地了解结核病纤维化的起源，我们使用结核肉芽肿生物学的计算模型来确定在局部疾病进展过程中驱动纤维化的因素。我们用非人灵长类动物的肉芽肿来验证该模型，以描述骨髓细胞和肺内的成纤维细胞。我们的研究结果表明，外周肉芽肿纤维化，这是常见的，可以通过巨噬细胞到肌成纤维细胞转化（MMT）。此外，我们假设MMT是通过肉芽肿巨噬细胞中炎症和抗炎信号的顺序组合在M1巨噬细胞中诱导的。我们预测MMT可能是肉芽肿相关纤维化的潜在机制，并需要进一步研究骨髓细胞作为纤维化疾病的驱动因素。结核病是由结核分枝杆菌（Mtb）引起的疾病，这种细菌感染了世界上三分之一以上的人口。唯一可用的结核病疫苗效力有限，药物治疗涉及服用数月的几种抗生素。这些药物可能具有显著的副作用，并且缺乏依从性可能导致Mtb的耐药性。Mtb感染的一个标志是在受感染的巨噬细胞周围形成细胞簇，以包含称为肉芽肿的感染。较老的肉芽肿，或用抗生素治疗的患者的肉芽肿，通常会变得纤维化，这可能会在结核分枝杆菌感染清除后很长时间内引起慢性肺部问题。导致纤维化结果的过程难以在体内评估。在这里，我们结合湿实验室和计算实验，以确定一种新的机制，导致周围纤维化的肉芽肿。我们发现巨噬细胞转化为肌纤维母细胞样细胞可能是肉芽肿相关纤维化的关键途径，这种现象在体内尚未得到很好的表征。此外，我们确定了可以抑制结核病期间纤维化发展的因素，这些因素可能是结核病治疗期间的治疗靶点，以限制结核病长期组织损伤的风险。
Mycobacterium tuberculosis (Mtb) infection causes tuberculosis (TB), a disease characterized by development of granulomas. Granulomas consist of activated immune cells that cluster together to limit bacterial growth and restrict dissemination. Control of the TB epidemic has been limited by lengthy drug regimens, antibiotic resistance, and lack of a robustly efficacious vaccine. Fibrosis commonly occurs during treatment and is associated with both positive and negative disease outcomes in TB but little is known about the processes that initiate fibrosis in granulomas. Human and nonhuman primate granulomas undergoing fibrosis can have spindle-shaped macrophages with fibroblast-like morphologies suggesting a relationship between macrophages, fibroblasts, and granuloma fibrosis. This relationship has been difficult to investigate because of the limited availability of human pathology samples, the time scale involved in human TB, and overlap between fibroblast and myeloid cell markers in tissues. To better understand the origins of fibrosis in TB, we used a computational model of TB granuloma biology to identify factors that drive fibrosis over the course of local disease progression. We validated the model with granulomas from nonhuman primates to delineate myeloid cells and lung-resident fibroblasts. Our results suggest that peripheral granuloma fibrosis, which is commonly observed, can arise through macrophage-to-myofibroblast transformation (MMT). Further, we hypothesize that MMT is induced in M1 macrophages through a sequential combination of inflammatory and anti-inflammatory signaling in granuloma macrophages. We predict that MMT may be a mechanism underlying granuloma-associated fibrosis and warrants further investigation into myeloid cells as drivers of fibrotic disease. Tuberculosis is a disease caused by Mycobacterium tuberculosis (Mtb), a bacterium that infects over a third of the world’s population. The only available vaccine for TB has limited efficacy and drug treatment involves several antibiotics that are taken for several months. These drugs can have significant side-effects and a lack of compliance can lead to drug resistance in Mtb. A hallmark of Mtb infection is the development of clusters of cells that form around infected macrophages to contain the infection called granulomas. Older granulomas, or granulomas in patients treated with antibiotic, often become fibrotic and this can cause chronic lung problems long after the Mtb infection has cleared. The process that drives a fibrotic outcome has been difficult to assess in vivo. Herein we combined wet-lab and computational experimentation to identify a novel mechanism leading to peripheral fibrosis in granulomas. We find that macrophages transforming into myofibroblast-like cells, may be a key pathway to granuloma-associated fibrosis, a phenomena that has not been well characterized in vivo. Further we identified factors that can inhibit fibrosis development during TB that could be therapeutic targets during TB treatment to limit the risk of long-term tissue damage in TB.
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影响因子：
8.7
作者：
Cicchese JM;Evans S;Hult C;Joslyn LR;Wessler T;Millar JA;Marino S;Cilfone NA;Mattila JT;Linderman JJ;Kirschner DE
通讯作者：
Kirschner DE
DOI：
10.4049/jimmunol.1300113
发表时间：
2013-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Mattila JT;Ojo OO;Kepka-Lenhart D;Marino S;Kim JH;Eum SY;Via LE;Barry CE 3rd;Klein E;Kirschner DE;Morris SM Jr;Lin PL;Flynn JL
通讯作者：
Flynn JL
影响因子：
82.9
作者：
Lin, Philana Ling;Ford, Christopher B.;Flynn, JoAnne L.
通讯作者：
Flynn, JoAnne L.
影响因子：
1.2
作者：
Koga, Masaaki;Kuramochi, Mizuki;Yamate, Jyoji
通讯作者：
Yamate, Jyoji
DOI：
10.1073/pnas.1121497109
发表时间：
2012-08-28
影响因子：
11.1
作者：
Lin, Philana Ling;Dartois, Veronique;Flynn, JoAnne L.
通讯作者：
Flynn, JoAnne L.