Galectin-3 functions as an alarmin: pathogenic role for sepsis development in murine respiratory tularemia.
Galectin-3 functions as an alarmin: pathogenic role for sepsis development in murine respiratory tularemia.
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DOI：
10.1371/journal.pone.0059616
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sharma J
中科院分区：
文献类型：
--
作者：
Mishra BB;Li Q;Steichen AL;Binstock BJ;Metzger DW;Teale JM;Sharma J
脓毒症是一种复杂的免疫性疾病，死亡率为 20-50%，目前尚无治疗干预措施。因此，识别和表征对其发展负责的分子/因素至关重要。我们最近表明，弗朗西斯菌的肺部感染会导致败血症的发生。由于广泛的细胞死亡是脓毒症的一个显着特征，我们假设从死亡或垂死的宿主细胞释放的称为警报素的宿主内源性分子会引起过度炎症反应，最终导致脓毒症的发展。在当前的研究中，我们研究了半乳糖凝集素-3（一种哺乳动物β-半乳糖苷结合凝集素）作为新凶手镰刀菌感染期间脓毒症发展中警报素的作用。我们观察到，在遭受新凶手F. novicida强毒株致死性肺部感染的小鼠的肺部中，半乳糖凝集素3的表达和细胞外释放上调，但在感染非致命性减毒菌株的小鼠中，galectin-3的表达和细胞外释放却没有上调。与野生型 C57Bl/6 对应物相比，F. novicida 感染的半乳糖凝集素 3 缺陷 (galectin-3−/−) 小鼠表现出白细胞浸润显着减少，特别是肺部的中性粒细胞。他们还表现出炎症细胞因子、血管损伤标志物和中性粒细胞相关炎症介质的显着减少。与此同时，用重组半乳糖凝集素 3 对原代中性粒细胞和巨噬细胞进行体外预处理，增强了新凶手 F. novicida 诱导的这些细胞的活化。与炎症反应减少相关，尽管细菌负荷相似，但与野生型小鼠相比，新恶杆菌感染的半乳糖凝集素-3−/−小鼠的肺结构有所改善，细胞死亡减少，存活率提高。总的来说，这些发现表明，galectin-3 通过增强肺部新凶手镰刀菌感染期间脓毒症发展中的炎症反应，发挥警报素的作用。
Sepsis is a complex immune disorder with a mortality rate of 20–50% and currently has no therapeutic interventions. It is thus critical to identify and characterize molecules/factors responsible for its development. We have recently shown that pulmonary infection with Francisella results in sepsis development. As extensive cell death is a prominent feature of sepsis, we hypothesized that host endogenous molecules called alarmins released from dead or dying host cells cause a hyperinflammatory response culminating in sepsis development. In the current study we investigated the role of galectin-3, a mammalian β-galactoside binding lectin, as an alarmin in sepsis development during F. novicida infection. We observed an upregulated expression and extracellular release of galectin-3 in the lungs of mice undergoing lethal pulmonary infection with virulent strain of F. novicida but not in those infected with a non-lethal, attenuated strain of the bacteria. In comparison with their wild-type C57Bl/6 counterparts, F. novicida infected galectin-3 deficient (galectin-3−/−) mice demonstrated significantly reduced leukocyte infiltration, particularly neutrophils in their lungs. They also exhibited a marked decrease in inflammatory cytokines, vascular injury markers, and neutrophil-associated inflammatory mediators. Concomitantly, in-vitro pre-treatment of primary neutrophils and macrophages with recombinant galectin-3 augmented F. novicida-induced activation of these cells. Correlating with the reduced inflammatory response, F. novicida infected galectin-3−/− mice exhibited improved lung architecture with reduced cell death and improved survival over wild-type mice, despite similar bacterial burden. Collectively, these findings suggest that galectin-3 functions as an alarmin by augmenting the inflammatory response in sepsis development during pulmonary F. novicida infection.
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DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
3.4
作者：
John, CM;Jarvis, GA;Griffiss, JM
通讯作者：
Griffiss, JM
影响因子：
7.3
作者：
Foell, D.;Wittkowski, H.;Clancy, R.
通讯作者：
Clancy, R.
影响因子：
2.8
作者：
Alves, Celene M. O. S.;Silva, Deise A. O.;Mineo, Jose R.
通讯作者：
Mineo, Jose R.
影响因子：
3.1
作者：
Mares, Chris A.;Ojeda, Sandra S.;Teale, Judy M.
通讯作者：
Teale, Judy M.