Bruton tyrosine kinase (BTK) is present in a wide variety of cells and may thus have important non–B cell functions. Here, we explored the function of this kinase in macrophages with studies of its regulation of the NLR family, pyrin domain–containing 3 (NLRP3) inflammasome. We found that bone marrow–derived macrophages (BMDMs) from BTK-deficient mice or monocytes from patients with X-linked agammaglobulinemia (XLA) exhibited increased NLRP3 inflammasome activity; this was also the case for BMDMs exposed to low doses of BTK inhibitors such as ibrutinib and for monocytes from patients with chronic lymphocytic leukemia being treated with ibrutinib. In mechanistic studies, we found that BTK bound to NLRP3 during the priming phase of inflammasome activation and, in doing so, inhibited LPS- and nigericin-induced assembly of the NLRP3 inflammasome during the activation phase of inflammasome activation. This inhibitory effect was caused by BTK inhibition of protein phosphatase 2A–mediated (PP2A-mediated) dephosphorylation of Ser5 in the pyrin domain of NLRP3. Finally, we show that BTK-deficient mice were subject to severe experimental colitis and that such colitis was normalized by administration of anti–IL-β or anakinra, an inhibitor of IL-1β signaling. Together, these studies strongly suggest that BTK functions as a physiologic inhibitor of NLRP3 inflammasome activation and explain why patients with XLA are prone to develop Crohn’s disease.

中文翻译：

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布鲁顿酪氨酸激酶缺乏症会增强NLRP3炎性小体的活化，并引起IL-1β介导的结肠炎。

布鲁顿酪氨酸激酶（BTK）存在于多种细胞中，因此可能具有重要的非B细胞功能。在这里，我们通过研究其对NLR家族的调控，研究了这种激酶在巨噬细胞中的功能，该家族含有3个pyrin结构域（NLRP3）炎症小体。我们发现，来自BTK缺陷型小鼠的骨髓巨噬细胞（BMDM）或来自X连锁无糖球蛋白血症（XLA）患者的单核细胞表现出更高的NLRP3炎性体活性。暴露于低剂量BTK抑制剂（如依鲁替尼）的BMDM以及接受依鲁替尼治疗的慢性淋巴细胞性白血病患者的单核细胞也是如此。在机理研究中，我们发现BTK在炎症小体激活的启动阶段与NLRP3结合，并且这样做 在炎症小体激活的激活阶段抑制LPS和尼日利亚霉素诱导的NLRP3炎症小体的组装。这种抑制作用是由BTK抑制NLRP3的pyrin结构域中的Ser5蛋白磷酸酶2A介导的（PP2A介导的）去磷酸化作用引起的。最后，我们证明了缺乏BTK的小鼠遭受了严重的实验性结肠炎，并且通过施用抗IL-β或anakinra（IL-1β信号的抑制剂）使这种结肠炎得以正常化。总之，这些研究强烈表明BTK可以作为NLRP3炎症小体激活的生理抑制剂，并解释了为什么XLA患者容易发生克罗恩病。这种抑制作用是由BTK抑制NLRP3的pyrin结构域中的蛋白磷酸酶2A介导（PP2A介导）的Ser5脱磷酸作用引起的。最后，我们证明了缺乏BTK的小鼠遭受了严重的实验性结肠炎，并且通过施用抗IL-β或anakinra（IL-1β信号的抑制剂）使这种结肠炎得以正常化。总之，这些研究强烈表明BTK可以作为NLRP3炎症小体激活的生理抑制剂，并解释了为什么XLA患者容易发生克罗恩病。这种抑制作用是由BTK抑制NLRP3的pyrin结构域中的Ser5蛋白磷酸酶2A介导的（PP2A介导的）去磷酸化作用引起的。最后，我们证明了缺乏BTK的小鼠遭受了严重的实验性结肠炎，并且通过施用抗IL-β或anakinra（IL-1β信号的抑制剂）使这种结肠炎得以正常化。总之，这些研究强烈表明BTK可以作为NLRP3炎症小体激活的生理抑制剂，并解释了为什么XLA患者容易发生克罗恩病。