结核分枝杆菌在感染的巨噬细胞中激活NLRP3-炎症小体需要溶酶体组织蛋白酶释放。,Frontiers in Immunology

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结核分枝杆菌在感染的巨噬细胞中激活NLRP3-炎症小体需要溶酶体组织蛋白酶释放。
Frontiers in Immunology ( IF 5.7 ) Pub Date : 2018-07-07 , DOI: 10.3389/fimmu.2018.01427
Eduardo P Amaral ₁ , Nicolas Riteau ₁ , Mahtab Moayeri ₁ , Nolan Maier ₁ , Katrin D Mayer-Barber ₂ , Rosana M Pereira ₃ , Silvia L Lage ₄ , Andre Kubler _{5,

6} , William R Bishai ₆ , Maria R D'Império-Lima ₃ , Alan Sher ₁ , Bruno B Andrade _{1,

7,

8,

9,

10,

11,

12}

Affiliation

Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
Laboratory of Immunology of Infectious Diseases, Department of Immunology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
Department of Medicine, Imperial College London, London, United Kingdom.
Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil.
Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, José Silveira Foundation, Salvador, Brazil.
Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States.
Universidade Salvador (UNIFACS), Laureate University, Salvador, Bahia, Brazil.
Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil.

已经提出了溶酶体组织蛋白酶B（CTSB）在诱导急性炎症中起作用。我们假设细胞质中活性CTSB的存在对于NLRP3炎症小体组装至关重要，因此对于体外分枝杆菌感染后成熟的IL-1β产生至关重要。在感染结核分枝杆菌（Mtb）H37Rv的小鼠和兔子的肺以及急性肺结核患者的血浆中，CTSB的水平升高。受H37Rv感染的鼠源性骨髓巨噬细胞（BMDM）表现出溶酶体渗漏，CTSB释放到细胞质中以及成熟IL-1β水平升高。在感染了ESAT-6表达缺陷的突变型H37Rv的BMDM中，这些反应减弱。CA074-Me对组织蛋白酶活性的药理抑制作用导致感染的巨噬细胞中成熟IL-1β的产生和caspase-1活化的显着降低。此外，通过在H37Rv感染的巨噬细胞中进行免疫荧光成像检测，组织蛋白酶的抑制作用消除了NLRP3与ASC之间的相互作用，这证明了该酶在NLRP3炎症小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的溶酶体释放以及可能受CA07-Me抑制的其他组织蛋白酶通过调节细胞质中的NLRP3-炎症小体装配，对于诱导炎症小体介导的IL-1β加工至关重要。在H37Rv感染的巨噬细胞中通过免疫荧光成像法检测到，证明了该酶在NLRP3炎症小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的溶酶体释放以及可能受CA07-Me抑制的其他组织蛋白酶通过调节细胞质中的NLRP3-炎症小体装配对诱导炎症小体介导的IL-1β加工至关重要。在H37Rv感染的巨噬细胞中通过免疫荧光成像法检测到，证明了该酶在NLRP3炎症小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的溶酶体释放以及可能受CA07-Me抑制的其他组织蛋白酶通过调节细胞质中的NLRP3-炎症小体装配对诱导炎症小体介导的IL-1β加工至关重要。

"点击查看英文标题和摘要"

Lysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by Mycobacterium tuberculosis in Infected Macrophages.

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.

更新日期：2019-11-01

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