NLR family, apoptosis inhibitory proteins (NAIPs) detect bacterial flagellin and structurally related components of bacterial type III secretion systems (T3SS), and recruit NLR family CARD domain containing protein 4 (NLRC4) and caspase-1 into an inflammasome complex that induces pyroptosis. NAIP/NLRC4 inflammasome assembly is initiated by the binding of a single NAIP to its cognate ligand, but a subset of bacterial flagellins or T3SS structural proteins are thought to evade NAIP/NLRC4 inflammasome sensing by not binding to their cognate NAIPs. Unlike other inflammasome components such as NLRP3, AIM2, or some NAIPs, NLRC4 is constitutively present in resting macrophages and not known to be induced by inflammatory signals. Here, we demonstrate that Toll-like receptor (TLR)-dependent p38 mitogen-activated protein kinase signaling up-regulates NLRC4 transcription and protein expression in murine macrophages, which licenses NAIP detection of evasive ligands. In contrast, TLR priming in human macrophages did not up-regulate NLRC4 expression, and human macrophages remained unable to detect NAIP-evasive ligands even following priming. Critically, ectopic expression of either murine or human NLRC4 was sufficient to induce pyroptosis in response to immunoevasive NAIP ligands, indicating that increased levels of NLRC4 enable the NAIP/NLRC4 inflammasome to detect these normally evasive ligands. Altogether, our data reveal that TLR priming tunes the threshold for the murine NAIP/NLRC4 inflammasome to enable inflammasome responses against immunoevasive or suboptimal NAIP ligands. These findings provide insight into species-specific TLR regulation of NAIP/NLRC4 inflammasome activation.

中文翻译：

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TLR 引发许可 NAIP 通过免疫逃避配体激活炎性小体


NLR 家族，凋亡抑制蛋白 （NAIP） 检测细菌鞭毛蛋白和细菌 III 型分泌系统 （T3SS） 的结构相关成分，并将包含蛋白 4 （NLRC4） 和 caspase-1 的 NLR 家族 CARD 结构域募集到诱导焦亡的炎性小体复合物中。NAIP/NLRC4 炎性小体组装是由单个 NAIP 与其同源配体的结合引发的，但细菌鞭毛蛋白或 T3SS 结构蛋白的一个子集被认为通过不与其同源 NAIP 结合来逃避 NAIP/NLRC4 炎性小体感应。与 NLRP3、AIM2 或一些 NAIP 等其他炎性小体成分不同，NLRC4 组成性存在于静息巨噬细胞中，未知是否由炎症信号诱导。在这里，我们证明了 Toll 样受体 （TLR） 依赖性 p38 丝裂原活化蛋白激酶信号转导上调小鼠巨噬细胞中的 NLRC4 转录和蛋白质表达，这允许 NAIP 检测逃避配体。相比之下，人巨噬细胞中的 TLR 引发不会上调 NLRC4 表达，即使在引发后，人巨噬细胞仍然无法检测到 NAIP 逃避配体。至关重要的是，小鼠或人 NLRC4 的异位表达足以诱导响应免疫逃避 NAIP 配体的焦亡，这表明 NLRC4 水平的增加使 NAIP/NLRC4 炎性小体能够检测这些正常逃避的配体。总而言之，我们的数据显示，TLR 启动会调整小鼠 NAIP/NLRC4 炎性小体的阈值，以使炎性小体对免疫逃避或不理想的 NAIP 配体产生反应。这些发现为 NAIP/NLRC4 炎性小体激活的物种特异性 TLR 调控提供了见解。