Lysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by Mycobacterium tuberculosis in Infected Macrophages.
Lysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by Mycobacterium tuberculosis in Infected Macrophages.
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DOI：
10.3389/fimmu.2018.01427
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发表时间：
2018
影响因子：
7.3
通讯作者：
Andrade BB
中科院分区：
文献类型：
--
作者：
Amaral EP;Riteau N;Moayeri M;Maier N;Mayer-Barber KD;Pereira RM;Lage SL;Kubler A;Bishai WR;D'Império-Lima MR;Sher A;Andrade BB
溶酶体组织蛋白酶B（CTSB）已被提出在急性炎症的诱导中发挥作用。我们假设细胞溶质中活性CTSB的存在对于NLRP 3-炎性小体组装至关重要，因此对于体外分枝杆菌感染后成熟IL-1β的产生至关重要。在感染结核分枝杆菌（Mtb）H37 Rv后的小鼠和家兔的肺中以及急性结核患者的血浆中观察到CTSB水平升高。H37 Rv感染的小鼠骨髓源性巨噬细胞（BMDM）显示出溶酶体渗漏，CTSB释放到细胞溶质中，以及成熟IL-1β水平升高。这些反应在感染ESAT-6表达缺陷的突变体H37 Rv的BMDM中减弱。用CA 074-Me对组织蛋白酶活性的药理学抑制导致感染的巨噬细胞中成熟IL-1β产生和半胱天冬酶-1活化的实质性减少。此外，组织蛋白酶抑制消除了NLRP 3和ASC之间的相互作用，在H37 Rv感染的巨噬细胞中通过免疫荧光成像测量，证明了该酶在NLRP 3-炎性体激活中的关键作用。这些观察结果表明，在Mtb感染期间，活化的CTSB和可能的其他CA 07-Me可降解的组织蛋白酶的溶酶体释放对于通过调节胞质溶胶中的NLRP 3-炎性小体组装来诱导炎性小体介导的IL-1β加工是关键的。
Lysosomal cathepsin B (CTSB) has been proposed to play a role in the induction of acute inflammation. We hypothesised that the presence of active CTSB in the cytosol is crucial for NLRP3-inflammasome assembly and, consequently, for mature IL-1β generation after mycobacterial infection in vitro. Elevated levels of CTSB was observed in the lungs of mice and rabbits following infection with Mycobacterium tuberculosis (Mtb) H37Rv as well as in plasma from acute tuberculosis patients. H37Rv-infected murine bone marrow-derived macrophages (BMDMs) displayed both lysosomal leakage, with release of CTSB into the cytosol, as well as increased levels of mature IL-1β. These responses were diminished in BMDM infected with a mutant H37Rv deficient in ESAT-6 expression. Pharmacological inhibition of cathepsin activity with CA074-Me resulted in a substantial reduction of both mature IL-1β production and caspase-1 activation in infected macrophages. Moreover, cathepsin inhibition abolished the interaction between NLRP3 and ASC, measured by immunofluorescence imaging in H37Rv-infected macrophages, demonstrating a critical role of the enzyme in NLRP3-inflammasome activation. These observations suggest that during Mtb infection, lysosomal release of activated CTSB and possibly other cathepsins inhibitable by CA07-Me is critical for the induction of inflammasome-mediated IL-1β processing by regulating NLRP3-inflammasome assembly in the cytosol.
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影响因子：
6.4
作者：
Junqueira-Kipnis, Ana Paula;Basaraba, Randall J.;Orme, Ian M.
通讯作者：
Orme, Ian M.
影响因子：
3.4
作者：
Koo, Ingrid C.;Wang, Chen;Brown, Eric J.
通讯作者：
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影响因子：
4.4
作者：
Hoegen, Tobias;Tremel, Nadin;Koedel, Uwe
通讯作者：
Koedel, Uwe
适配器 ASC 具有传播炎症的细胞外活性和“prionoid”活性。
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
4.2
作者：
Amaral EP;Conceição EL;Costa DL;Rocha MS;Marinho JM;Cordeiro-Santos M;D'Império-Lima MR;Barbosa T;Sher A;Andrade BB
通讯作者：
Andrade BB