Human Monocytes Engage an Alternative Inflammasome Pathway
Human Monocytes Engage an Alternative Inflammasome Pathway
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DOI：
10.1016/j.immuni.2016.01.012
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发表时间：
2016-04-19
期刊：
影响因子：
32.4
通讯作者：
Hornung, Veit
中科院分区：
文献类型：
--
作者：
Gaidt, Moritz M.;Ebert, Thomas S.;Hornung, Veit
白细胞介素-1 β（IL-1 β）是一种细胞因子，其生物活性受炎性小体的激活控制。然而，响应于脂多糖，人单核细胞独立于经典炎性体刺激而分泌IL-1 β。在这里，我们报告说，这构成了一个物种特异性的反应，是没有观察到的小鼠系统。事实上，在人单核细胞中，脂多糖触发了依赖于NLRP 3-ASC-半胱天冬酶-1信号传导的“替代性炎性小体”，但缺乏任何经典的炎性小体特征，包括焦浆体形成、焦亡诱导和K+流出依赖性。在单核细胞转分化系统中的潜在信号传导途径的遗传解剖揭示了通过NLRP 3上游的TLR 4-TRIF-RIPK 1-FADD-CASP 8信号传导传播替代性炎性小体激活。重要的是，这种信号级联的参与仅限于替代性炎性小体激活，并没有扩展到经典的NLRP 3激活。由于替代性炎性小体激活包含TLR 4的敏感性和混杂性，因此我们提出了这种信号级联在人类TLR 4驱动的IL-1 β介导的免疫应答和免疫病理学中的关键作用。
Interleukin-1 beta (IL-1 beta) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1 beta independently of classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an "alternative inflammasome" that relied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristics including pyroptosome formation, pyroptosis induction, and K+ efflux dependency. Genetic dissection of the underlying signaling pathway in a monocyte transdifferentiation system revealed that alternative inflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream of NLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasome activation and did not extend to classical NLRP3 activation. Because alternative inflammasome activation embraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade in TLR4-driven, IL-1 beta-mediated immune responses and immunopathology in humans.