Increased autophagic sequestration in adaptor protein-3 deficient dendritic cells limits inflammasome activity and impairs antibacterial immunity.
Increased autophagic sequestration in adaptor protein-3 deficient dendritic cells limits inflammasome activity and impairs antibacterial immunity.
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DOI：
10.1371/journal.ppat.1006785
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发表时间：
2017-12
期刊：
影响因子：
6.7
通讯作者：
Marks MS
中科院分区：
文献类型：
--
作者：
Mantegazza AR;Wynosky-Dolfi MA;Casson CN;Lefkovith AJ;Shin S;Brodsky IE;Marks MS
危害吞噬体膜的细菌病原体刺激炎性小体在胞质溶胶中的组装，但膜动力学调节炎性小体活性的分子机制的特征很差。我们表明，在小鼠树突状细胞（DC）中，内体衔接蛋白AP-3（优化来自吞噬体的toll样受体信号传导）维持颗粒刺激引起的炎性小体激活。AP-3独立地调节炎性体定位和自噬诱导，共同导致响应于鼠伤寒沙门氏菌（STm）和其他颗粒刺激物的自噬的延迟炎性体失活，特别是在DC中。AP-3缺陷型DC（而非巨噬细胞）在体外响应于颗粒刺激而分泌IL-1β和IL-18减少，但caspase-1和IL-1β水平通过沉默自噬而恢复。同时，AP-3缺陷型小鼠在口服STm感染后表现出比对照组更高的死亡率和产生更少的IL-1β、IL-18和IL-17。我们的数据确定了DC中吞噬作用、炎性小体活性和自噬之间的新联系，可能解释AP-3缺陷患者的抗菌免疫受损。吞噬细胞如树突状细胞（DC）的细菌摄取刺激来自膜结合的Toll样受体（TLR）的信号传导以形成适应性免疫应答。破坏吞噬细胞膜的病原菌还刺激细胞质炎性体，产生高度炎性细胞因子IL-1β和IL-18。宿主的分子机制，连接吞噬体信号炎症调节的特点很差。我们发现，在树突状细胞中，内体衔接蛋白-3（AP-3）复合物通过两种机制优化吞噬诱导的炎性小体活性：AP-3促进炎性小体组分的TLR信号转导依赖性转录和拮抗自噬依赖性炎性小体沉默。因此，AP-3缺陷型DC响应于吞噬刺激而分泌IL-1β和IL-18不足，并且AP-3缺陷型小鼠死于细菌病原体的感染。因此，AP-3将DC中的吞噬体信号传导、炎性体活性和自噬联系起来。
Bacterial pathogens that compromise phagosomal membranes stimulate inflammasome assembly in the cytosol, but the molecular mechanisms by which membrane dynamics regulate inflammasome activity are poorly characterized. We show that in murine dendritic cells (DCs), the endosomal adaptor protein AP-3 –which optimizes toll-like receptor signaling from phagosomes–sustains inflammasome activation by particulate stimuli. AP-3 independently regulates inflammasome positioning and autophagy induction, together resulting in delayed inflammasome inactivation by autophagy in response to Salmonella Typhimurium (STm) and other particulate stimuli specifically in DCs. AP-3-deficient DCs, but not macrophages, hyposecrete IL-1β and IL-18 in response to particulate stimuli in vitro, but caspase-1 and IL-1β levels are restored by silencing autophagy. Concomitantly, AP-3-deficient mice exhibit higher mortality and produce less IL-1β, IL-18, and IL-17 than controls upon oral STm infection. Our data identify a novel link between phagocytosis, inflammasome activity and autophagy in DCs, potentially explaining impaired antibacterial immunity in AP-3-deficient patients. Bacterial uptake by phagocytic cells such as dendritic cells (DCs) stimulates signaling from membrane-bound toll-like receptors (TLRs) to shape adaptive immune responses. Pathogenic bacteria that damage phagocytic membranes additionally stimulate the cytoplasmic inflammasome, producing the highly inflammatory cytokines IL-1β and IL-18. Host molecular mechanisms that link phagosomal signaling to inflammasome regulation are poorly characterized. We show that in DCs, the endosomal adaptor protein-3 (AP-3) complex optimizes phagocytosis-induced inflammasome activity by two mechanisms: AP-3 promotes TLR signaling-dependent transcription of inflammasome components and antagonizes autophagy-dependent inflammasome silencing. Consequently, AP-3 deficient DCs hyposecrete IL-1β and IL-18 in response to phagocytosed stimuli, and AP-3 deficient mice succumb to infection by a bacterial pathogen. AP-3 thus links phagosome signaling, inflammasome activity and autophagy in DCs.
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朊病毒样聚合是抗病毒免疫防御和炎症小体激活中信号转导的基础。
影响因子：
64.5
作者：
Cai X;Chen J;Xu H;Liu S;Jiang QX;Halfmann R;Chen ZJ
通讯作者：
Chen ZJ
DOI：
10.1083/jcb.200201081
发表时间：
2002-03-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Glomski IJ;Gedde MM;Tsang AW;Swanson JA;Portnoy DA
通讯作者：
Portnoy DA
影响因子：
8.7
作者：
Horvath GL;Schrum JE;De Nardo CM;Latz E
通讯作者：
Latz E
影响因子：
5.5
作者：
Gardella, S;Andrei, C;Rubartelli, A
通讯作者：
Rubartelli, A
影响因子：
100.3
作者：
Blander, J. Magarian;Sander, Leif E.
通讯作者：
Sander, Leif E.