Fibrinogen Regulates the Cytotoxicity of Mycobacterial Trehalose Dimycolate but Is Not Required for Cell Recruitment, Cytokine Response, or Control of Mycobacterial Infection
Fibrinogen Regulates the Cytotoxicity of Mycobacterial Trehalose Dimycolate but Is Not Required for Cell Recruitment, Cytokine Response, or Control of Mycobacterial Infection
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DOI：
10.1128/iai.00451-09
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发表时间：
2010-03-01
影响因子：
3.1
通讯作者：
Rhoades, Elizabeth R.
中科院分区：
文献类型：
--
作者：
Sakamoto, Kaori;Geisel, Rachel E.;Rhoades, Elizabeth R.
在炎症反应和伤口愈合过程中，可溶性纤维蛋白原转化为纤维蛋白（一种不溶性的细胞外基质），长期以来被认为是白细胞和成纤维细胞迁移的支架。先前的研究得出结论，纤维蛋白原是分枝杆菌海藻糖6,6'-二mycol酸诱导反应的必要辅助因子，因为纤维蛋白原被海藻糖二mycol酸包被的微球比其他血浆蛋白被吸附的微球更具有炎症性。在此，我们研究了纤维蛋白（原）在分枝杆菌肉芽肿形成的体内模型和结核分枝杆菌感染中的作用，结核的病原体。在野生型小鼠中，皮下注射海藻糖二聚乳酸包被的聚苯乙烯微球，悬浮在Matrigel中，在12天的过程中引起了脓肉芽肿反应。在纤维蛋白原缺乏的小鼠中，中性粒细胞被募集，但出现了更化脓性的病变，基质明显降解和解体。与野生型小鼠相比，纤维蛋白原缺乏小鼠肉芽组织的早期形成是水肿、低细胞和无组织的。这些缺陷通过添加外源性纤维蛋白原来补充。纤维蛋白原的缺乏对海藻糖二真菌酸反应的细胞募集或细胞因子产生没有影响，感染结核分枝杆菌的小鼠的肺组织病理学或总体细菌负荷也没有差异。在该模型中，纤维蛋白（原）不需要用于细胞募集、细胞因子反应或对感染的反应，但它促进肉芽组织形成并抑制白细胞坏死。
During inflammatory responses and wound healing, the conversion of soluble fibrinogen to fibrin, an insoluble extracellular matrix, long has been assumed to create a scaffold for the migration of leukocytes and fibroblasts. Previous studies concluded that fibrinogen is a necessary cofactor for mycobacterial trehalose 6,6'-dimycolate-induced responses, because trehalose dimycolate-coated beads, to which fibrinogen was adsorbed, were more inflammatory than those to which other plasma proteins were adsorbed. Herein, we investigate roles for fibrin(ogen) in an in vivo model of mycobacterial granuloma formation and in infection with Mycobacterium tuberculosis, the causative agent of tuberculosis. In wild-type mice, the subcutaneous injection of trehalose dimycolate-coated polystyrene microspheres, suspended within Matrigel, elicited a pyogranulomatous response during the course of 12 days. In fibrinogen-deficient mice, neutrophils were recruited but a more suppurative lesion developed, with the marked degradation and disintegration of the matrix. Compared to that in wild-type mice, the early formation of granulation tissue in fibrinogen-deficient mice was edematous, hypocellular, and disorganized. These deficiencies were complemented by the addition of exogenous fibrinogen. The absence of fibrinogen had no effect on cell recruitment or cytokine production in response to trehalose dimycolate, nor was there a difference in lung histopathology or overall bacterial burden in mice infected with Mycobacterium tuberculosis. In this model, fibrin(ogen) was not required for cell recruitment, cytokine response, or response to infection, but it promoted granulation tissue formation and suppressed leukocyte necrosis.