PDF(Pubmed)
Abstract：
TLR4 and TNFR1 signalling promotes potent proinflammatory signal transduction events, thus, are often hijacked by pathogenic microorganisms. We recently reported that myeloid cells retaliate Yersinia blockade of TAK1/IKK signalling by triggering RIPK1-dependent caspase-8 activation that promotes downstream GSDMD and GSDME-mediated pyroptosis in macrophages and neutrophils respectively. However, the upstream signalling events for RIPK1 activation in these cells are not well defined. Here, we demonstrate that unlike in macrophages, RIPK1-driven pyroptosis and cytokine priming in neutrophils are driven through TNFR1 signalling, while TLR4-TRIF signalling is dispensable. Furthermore, we demonstrate that activation of RIPK1-dependent pyroptosis in neutrophils during Yersinia infection requires IFN-γ priming, which serves to induce surface TNFR1 expression and amplify soluble TNF secretion. In contrast, macrophages utilise both TNFR1 and TLR4-TRIF signalling to trigger cell death, but only require TRIF but not autocrine TNFR1 for cytokine production. Together, these data highlight the emerging theme of cell type-specific regulation in cell death and immune signalling in myeloid cells.
摘要：
TLR4和TNFR1信号促进有效的促炎信号转导事件，因此，经常被病原微生物劫持。我们最近报道，骨髓细胞通过触发RIPK1依赖性caspase-8激活来报复耶尔森氏菌对TAK1/IKK信号传导的阻断，该激活分别促进下游GSDMD和GSDME介导的巨噬细胞和中性粒细胞的焦亡。然而,这些细胞中RIPK1激活的上游信号事件没有很好的定义。这里,我们证明了与巨噬细胞不同，RIPK1驱动的嗜中性粒细胞中的焦亡和细胞因子启动是通过TNFR1信号驱动的，而TLR4-TRIF信号是可有可无的。此外，我们证明，在耶尔森氏菌感染期间，嗜中性粒细胞中RIPK1依赖性焦亡的激活需要IFN-γ引发，其用于诱导表面TNFR1表达和扩增可溶性TNF分泌。相比之下,巨噬细胞利用TNFR1和TLR4-TRIF信号触发细胞死亡，但只需要TRIF而不是自分泌TNFR1来产生细胞因子。一起,这些数据突出了骨髓细胞死亡和免疫信号中细胞类型特异性调节的新兴主题.
