Trypanosoma cruzi High Mobility Group B (TcHMGB) can act as an inflammatory mediator on mammalian cells.
Trypanosoma cruzi High Mobility Group B (TcHMGB) can act as an inflammatory mediator on mammalian cells.
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DOI：
10.1371/journal.pntd.0005350
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发表时间：
2017-02
影响因子：
3.8
通讯作者：
Hernández-Pando R
中科院分区：
文献类型：
--
作者：
Cribb P;Perdomo V;Alonso VL;Manarin R;Barrios-Payán J;Marquina-Castillo B;Tavernelli L;Hernández-Pando R
高迁移率族B（HMGB）蛋白是参与染色质重塑和重要核事件的核结构因子。HMGBs也在细胞外发挥关键作用，作为警报或损伤相关分子模式（DAMP）。在对危险信号的反应中，这些蛋白质在细胞外环境中充当免疫介质。此外，这些分子在许多自身免疫性以及感染性和无菌性炎症性慢性疾病的发病机制中起着核心作用。我们先前已经从克氏锥虫（Trypanosoma cruzi，TcHMGB）中鉴定出高迁移率族B蛋白，并表明它具有与来自其他真核生物的DNA类似的HMGB相互作用的结构特性。在这里，我们表明，TcHMGB可以易位到细胞质和分泌的寄生虫，这一过程似乎是由乙酰化刺激。我们报道了重组TcHMGB能够在体外和体内诱导炎症反应，通过产生一氧化氮和诱导炎性细胞因子如TNF-α、IL-1β和IFN-γ基因表达来证明。此外，TGF-β和IL-10，这不是炎性细胞因子，但确实在查加斯病中发挥关键作用，由rTcHMGB诱导。这些初步结果表明，TcHMGB可以作为一种外源性免疫介质，可能是重要的控制寄生虫复制的南美锥虫病的发病机制，并可以设想为病原体相关的分子模式（PAMP）部分重叠的功能与主机DAMP。当感染发生时，先天免疫细胞通过其模式识别受体识别病原体相关分子模式（PAMP）。这会引发炎症反应，旨在杀死外来微生物。但是炎症也可以通过识别称为“危险（或损伤）相关分子模式”（DAMP）的内源性分子来触发，这些分子由受损或坏死的细胞释放，以“敲响免疫系统需要修复的警报”，因此其中一些也被称为“警报”。高迁移率族蛋白1（HMGB 1）是由受损细胞释放的原型警报蛋白分子，并且其也由先天免疫系统的细胞响应于入侵以及无菌损伤而主动分泌。克氏锥虫是南美锥虫病的病原体，它有自己的HMGB蛋白，我们称之为TcHMGB。使用体外和体内实验系统，我们首次证明了TcHMGB能够介导哺乳动物细胞的炎症，诱导促炎和抗炎细胞因子的表达。我们的研究结果表明，寄生虫的蛋白质可能在免疫反应和恰加斯病的发病机制中发挥作用，可能在某种程度上与宿主细胞DAMP分子的功能重叠。
High Mobility Group B (HMGB) proteins are nuclear architectural factors involved in chromatin remodeling and important nuclear events. HMGBs also play key roles outside the cell acting as alarmins or Damage-associated Molecular Patterns (DAMPs). In response to a danger signal these proteins act as immune mediators in the extracellular milieu. Moreover, these molecules play a central role in the pathogenesis of many autoimmune and both infectious and sterile inflammatory chronic diseases. We have previously identified a High mobility group B protein from Trypanosoma cruzi (TcHMGB) and showed that it has architectural properties interacting with DNA like HMGBs from other eukaryotes. Here we show that TcHMGB can be translocated to the cytoplasm and secreted out of the parasite, a process that seems to be stimulated by acetylation. We report that recombinant TcHMGB is able to induce an inflammatory response in vitro and in vivo, evidenced by the production of Nitric Oxide and induction of inflammatory cytokines like TNF-α, IL-1β and IFN-γ gene expression. Also, TGF-β and IL-10, which are not inflammatory cytokines but do play key roles in Chagas disease, were induced by rTcHMGB. These preliminary results suggest that TcHMGB can act as an exogenous immune mediator that may be important for both the control of parasite replication as the pathogenesis of Chagas disease and can be envisioned as a pathogen associated molecular pattern (PAMP) partially overlapping in function with the host DAMPs. When an infection occurs, the innate immune cells recognize Pathogen Associated Molecular Patterns (PAMPs) through their Pattern Recognition Receptors. This triggers an inflammatory response intended to kill the foreign microbe. But inflammation can also be triggered by the recognition of endogenous molecules called “Danger (or Damage) Associated Molecular Patterns” (DAMPs) that are released by damaged or necrotic cells to “ring the alarm” of the immune system that repair is needed, so some of them are also known as “alarmins”. High Mobility group box 1 protein (HMGB1) is a prototypical alarmin molecule released by injured cells and it is also actively secreted by cells of the innate immune system in response to invasion as well as to sterile damage. Trypanosoma cruzi, the causal agent of Chagas Disease, has its own HMGB protein that we called TcHMGB. Using in vitro and in vivo experimental systems, we demonstrated for the first time that TcHMGB is able to mediate inflammation on mammalian cells, inducing the expression of both pro-inflammatory and anti-inflammatory cytokines. Our results suggest that the parasite´s protein could have a role in the immune response and the pathogenesis of Chagas disease, probably overlapping to some extent with the host cell DAMP molecules´ functions.
影响因子：
2
作者：
Thirugnanam S;Munirathinam G;Veerapathran A;Dakshinamoorthy G;Reddy MV;Ramaswamy K
通讯作者：
Ramaswamy K
影响因子：
3.7
作者：
Ferrão PM;de Oliveira FL;Degrave WM;Araujo-Jorge TC;Mendonça-Lima L;Waghabi MC
通讯作者：
Waghabi MC