Department of Life Science, National Taiwan University, Taipei 10617, Taiwan.
Genome and Systems Biology Degree Program, National Taiwan University, Taipei 10617, Taiwan.
Int J Mol Sci. 2020 Feb 14;21(4):1302. doi: 10.3390/ijms21041302.
Inflammasomes are intracellular multiple protein complexes that mount innate immune responses to tissue damage and invading pathogens. Their excessive activation is crucial in the development and pathogenesis of inflammatory disorders. Microtubules have been reported to provide the platform for mediating the assembly and activation of NLRP3 inflammasome. Recently, we have identified the microtubule-associated immune molecule guanine nucleotide exchange factor-H1 (GEF-H1) that is crucial in coupling microtubule dynamics to the initiation of microtubule-mediated immune responses. However, whether GEF-H1 also controls the activation of other immune receptors that require microtubules is still undefined. Here we employed GEF-H1-deficient mouse bone marrow-derived macrophages (BMDMs) to interrogate the impact of GEF-H1 on the activation of NLRP3 inflammasome. NLRP3 but not NLRC4 or AIM2 inflammasome-mediated IL-1β production was dependent on dynamic microtubule network in wild-type (WT) BMDMs. However, GEF-H1 deficiency did not affect NLRP3-driven IL-1β maturation and secretion in macrophages. Moreover, α-tubulin acetylation and mitochondria aggregations were comparable between WT and GEF-H1-deficient BMDMs in response to NLRP3 inducers. Further, GEF-H1 was not required for NLRP3-mediated immune defense against infection. Collectively, these findings suggest that the microtubule-associated immune modulator GEF-H1 is dispensable for microtubule-mediated NLRP3 activation and host defense in mouse macrophages.
炎症小体是一种细胞内的多蛋白复合物，可对组织损伤和入侵病原体产生先天免疫反应。它们的过度激活在炎症性疾病的发展和发病机制中至关重要。已有报道称微管为介导 NLRP3 炎症小体的组装和激活提供了平台。最近，我们鉴定了微管相关免疫分子鸟嘌呤核苷酸交换因子-H1（GEF-H1），它在将微管动力学与微管介导的免疫反应的启动偶联中起着至关重要的作用。然而，GEF-H1 是否还控制其他需要微管的免疫受体的激活仍未确定。在这里，我们使用 GEF-H1 缺陷型小鼠骨髓来源的巨噬细胞（BMDM）来研究 GEF-H1 对 NLRP3 炎症小体激活的影响。在野生型（WT）BMDM 中，NLRP3 但不是 NLRC4 或 AIM2 炎症小体介导的 IL-1β 产生依赖于动态微管网络。然而，GEF-H1 缺陷并不影响巨噬细胞中 NLRP3 驱动的 IL-1β 成熟和分泌。此外，WT 和 GEF-H1 缺陷型 BMDM 对 NLRP3 诱导剂的反应中，α-微管蛋白乙酰化和线粒体聚集相似。此外，GEF-H1 对于 NLRP3 介导的对 感染的免疫防御也不是必需的。综上所述，这些发现表明，微管相关免疫调节剂 GEF-H1 对于小鼠巨噬细胞中微管介导的 NLRP3 激活和宿主防御是可有可无的。
