Brucella abortus Infection Elicited Hepatic Stellate Cell-Mediated Fibrosis Through Inflammasome-Dependent IL-1β Production
Brucella abortus Infection Elicited Hepatic Stellate Cell-Mediated Fibrosis Through Inflammasome-Dependent IL-1β Production
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DOI：
10.3389/fimmu.2019.03036
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发表时间：
2020-01-21
影响因子：
7.3
通讯作者：
Victoria Delpino, Maria
中科院分区：
文献类型：
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作者：
Arriola Benitez, Paula Constanza;Pesce Viglietti, Ayelen Ivan;Victoria Delpino, Maria
在人类布鲁氏菌病中，肝脏经常受到影响。流产布鲁氏菌引发肝星状细胞（hsc）的纤维化反应，其特征是抑制MMP-9，同时伴有胶原沉积和tgf - β 1通过4型分泌系统（T4SS）分泌。考虑到有报道称炎症小体是诱导HSC纤维化表型所必需的，我们假设布鲁氏菌感染可能会创造一个微环境，促进炎症小体的激活，同时在HSC中出现促纤维化表型。B. abortus感染诱导造血干细胞以t4ss依赖性方式分泌IL-1 β。在黑素瘤2 （AIM2）中缺失的caspase-1 （Casp-1）、含有pyrin结构域3的nod样受体（NLR） （NLRP3）和含有CARD的凋亡相关斑点样蛋白（ASC）的表达在流产b感染的HSC中增加。当在格列本脲（一种抑制NLRP3炎性体的化合物）或A151（一种特异性AIM2抑制剂）存在的情况下进行感染实验时，与未感染的对照组相比，IL-1 β的分泌明显受到抑制。通过在抑制剂Ac-YVAD-cmk和格列本脲存在的情况下进行B. abortus感染实验，确定了炎症小体激活在诱导hsc纤维化表型中的作用。两种抑制剂都能逆转流产芽孢杆菌感染对造血干细胞纤维化表型的影响。最后，与感染的野生型小鼠相比，B. abortabors感染的ASC、NLRP、AIM2和cCasp-1/11敲除（KO）小鼠肝脏中纤维化斑块的减少证实了炎性体在纤维化中的作用。
In human brucellosis, the liver is frequently affected. Brucella abortus triggers a profibrotic response on hepatic stellate cells (HSCs) characterized by inhibition of MMP-9 with concomitant collagen deposition and TGF-beta 1 secretion through type 4 secretion system (T4SS). Taking into account that it has been reported that the inflammasome is necessary to induce a fibrotic phenotype in HSC, we hypothesized that Brucella infection might create a microenvironment that would promote inflammasome activation with concomitant profibrogenic phenotype in HSCs. B. abortus infection induces IL-1 beta secretion in HSCs in a T4SS-dependent manner. The expression of caspase-1 (Casp-1), absent in melanoma 2 (AIM2), Nod-like receptor (NLR) containing a pyrin domain 3 (NLRP3), and apoptosis-associated speck-like protein containing a CARD (ASC) was increased in B. abortus-infected HSC. When infection experiments were performed in the presence of glyburide, a compound that inhibits NLRP3 inflammasome, or A151, a specific AIM2 inhibitor, the secretion of IL-1 beta was significantly inhibited with respect to uninfected controls. The role of inflammasome activation in the induction of a fibrogenic phenotype in HSCs was determined by performing B. abortus infection experiments in the presence of the inhibitors Ac-YVAD-cmk and glyburide. Both inhibitors were able to reverse the effect of B. abortus infection on the fibrotic phenotype in HSCs. Finally, the role of inflammasome in fibrosis was corroborated in vivo by the reduction of fibrotic patches in liver from B. abortus-infected ASC, NLRP, AIM2, and cCasp-1/11 knock-out (KO) mice with respect to infected wild-type mice.