CD13 restricts TLR4 endocytic signal transduction in inflammation.
CD13 restricts TLR4 endocytic signal transduction in inflammation.
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DOI：
10.4049/jimmunol.1403133
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发表时间：
2015-05-01
期刊：
影响因子：
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通讯作者：
Shapiro LH
中科院分区：
文献类型：
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作者：
Ghosh M;Subramani J;Rahman MM;Shapiro LH
先天免疫反应的失调是许多病理条件的基础。toll样受体4 （TLR4）是感染或损伤的典型传感器，它通过细胞表面和内吞信号通路的顺序激活来协调先天反应，从而引发不同的下游后果。CD14结合并将LPS传递给TLR4，并已被确定为TLR4信号转导的正调节因子。这是合乎逻辑的，这个过程的负调节也存在，以维持对抗感染，愈合受损组织和解决炎症所需的关键平衡。我们发现CD13负调节树突状细胞中受体介导的银摄取来控制适应性免疫中的t细胞活化。在这里，我们报告髓细胞CD13控制TLR4的内化和随后的先天信号级联，独立于CD14激活IRF-3。在LPS处理下，CD13与TLR4、CD14和动力蛋白共同内化到Rab5+早期内体中。重要的是，在TLR4配体HMGB1和LPS的作用下，在CD13KO dc中，pIRF-3靶基因的激活和转录增强，而TLR4表面信号传导不受影响，导致炎症反应偏斜。这一发现在生理上是相关的，因为体内缺血性损伤引起了相同的TLR4反应。最后，CD13KO小鼠通过JAK-STAT显著增强ifn β介导的信号转导，升高iNOS转录水平，促进氧化应激介质的积累和组织损伤。从机制上讲，巨噬细胞的炎症激活上调CD13表达，CD13和TLR4共同免疫沉淀。因此，CD13负调控TLR4信号，从而通过维持对先天免疫调节至关重要的炎症平衡来平衡先天反应。
Dysregulation of the innate immune response underlies numerous pathological conditions. The Toll-like Receptor 4 (TLR4) is the prototypical sensor of infection or injury that orchestrates the innate response via sequential activation of both cell-surface and endocytic signaling pathways that trigger distinct downstream consequences. CD14 binds and delivers LPS to TLR4 and has been identified as a positive regulator of TLR4 signal transduction. It is logical that negative regulators of this process also exist to maintain the critical balance required for fighting infection, healing damaged tissue and resolving inflammation. We showed that CD13 negatively modulates receptor-mediated Ag uptake in dendritic cells to control T-cell activation in adaptive immunity. Here we report that myeloid CD13 governs internalization of TLR4 and subsequent innate signaling cascades, activating IRF-3 independently of CD14. CD13 is co-internalized with TLR4, CD14 and dynamin into Rab5+ early endosomes upon LPS treatment. Importantly, in response to TLR4 ligands HMGB1 and LPS, pIRF-3 activation and transcription of its target genes is enhanced in CD13KO DCs while TLR4 surface signaling remains unaffected, resulting in a skewed inflammatory response. This finding is physiologically relevant as ischemic injury in vivo provoked identical TLR4 responses. Finally, CD13KO mice showed significantly enhanced IFNβ-mediated signal transduction via JAK-STAT, escalating iNOS transcription levels and promoting accumulation of oxidative stress mediators and tissue injury. Mechanistically, inflammatory activation of macrophages upregulates CD13 expression and CD13 and TLR4 co-immunoprecipitate. Therefore, CD13 negatively regulates TLR4 signaling, thereby balancing the innate response by maintaining the inflammatory equilibrium critical to innate immune regulation.