Autotaxin (ATX) converts lysophosphatidylcholine and sphingosyl‐phosphorylcholine into lysophosphatidic acid and sphingosine 1‐phosphate, respectively. Despite the pivotal function of ATX in lipid metabolism, mechanisms by which ATX regulates immune and inflammatory disorders remain elusive. Here, using myeloid cell lineage‐restricted Atx knockout mice, we show that Atx deficiency disrupts membrane microdomains and lipid rafts, resulting in the inhibition of Toll‐like receptor 4 (TLR4) complex formation and the suppression of adaptor recruitment, thereby inhibiting TLR4‐mediated responses in macrophages. Accordingly, TLR4‐induced innate immune functions, including phagocytosis and iNOS expression, are attenuated in Atx‐deficient macrophages. Consequently, Atx^−/− mice exhibit a higher bacterial prevalence in the intestinal mucosa compared to controls. When combined with global Il10^−/− mice, which show spontaneous colitis due to the translocation of luminal commensal microbes into the mucosa, myeloid cell lineage‐restricted Atx knockout accelerates colitis development compared to control littermates. Collectively, our data reveal that Atx deficiency compromises innate immune responses, thereby promoting microbe‐associated gut inflammation.

中文翻译：

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自分泌运动因子损失通过抑制 TLR4 介导的免疫反应加速肠道炎症。

自分泌运动因子 (ATX) 将溶血磷脂酰胆碱和鞘氨醇磷酰胆碱分别转化为溶血磷脂酸和 1-磷酸鞘氨醇。尽管 ATX 在脂质代谢中具有关键作用，但 ATX 调节免疫和炎症疾病的机制仍然难以捉摸。在这里，使用骨髓细胞谱系限制性 Atx 基因敲除小鼠，我们表明 Atx 缺陷会破坏膜微区和脂筏，导致 Toll 样受体 4 (TLR4) 复合物形成的抑制和接头募集的抑制，从而抑制 TLR4-巨噬细胞介导的反应。因此，TLR4 诱导的先天免疫功能，包括吞噬作用和 iNOS 表达，在 Atx 缺陷的巨噬细胞中减弱。因此，Atx ^-/-与对照组相比，小鼠在肠粘膜中表现出更高的细菌流行率。当与全局 Il10 ^-/-小鼠结合时，由于管腔共生微生物易位到粘膜中而显示自发性结肠炎，与对照同窝仔相比，髓样细胞谱系限制性 Atx 敲除加速了结肠炎的发展。总的来说，我们的数据表明 Atx 缺乏会损害先天免疫反应，从而促进微生物相关的肠道炎症。