NLRP3 炎性小体作为一种传感器，可检测线粒体 SRC 家族激酶的低活性。

The NLRP3 Inflammasome Works as a Sensor for Detecting Hypoactivity of the Mitochondrial Src Family Kinases.

机构信息

Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

出版信息

J Immunol. 2023 Mar 15;210(6):795-806. doi: 10.4049/jimmunol.2200611.

DOI:10.4049/jimmunol.2200611

Abstract

Gefitinib (GF), the tyrosine kinase inhibitor (TKI) targeting epidermal growth factor receptor, initiates lung inflammation through the NLR family pyrin domain containing 3 (NLRP3) inflammasome. However, the molecular targets and mechanisms underlying the inflammatory action of GF remain unknown. In this study, we identified mitochondrial Src family kinases (mSFKs) as key determinants of GF-induced NLRP3 inflammasome activation. Comprehensive analysis of the TKIs revealed that all TKIs we tested act as potent agonists for the NLRP3 inflammasome in human monocytic THP-1 cells and bone marrow-derived macrophages. Moreover, these TKIs share a common off-target activity against the mSFKs, such as c-Src, Fgr, and Fyn. Interestingly, loss of each kinase spontaneously stimulated the NLRP3 inflammasome activation in THP-1 cells. These results together suggest that NLRP3 senses hypoactivity of the mSFKs that is responsible for mitochondrial dysfunction. Thus, our findings demonstrate a mechanistic link between the NLRP3 inflammasome and mSFKs, which, to our knowledge, provides insights into a novel molecular basis and cellular function of the NLRP3 inflammasome.

摘要

吉非替尼（GF）是一种针对表皮生长因子受体的酪氨酸激酶抑制剂（TKI），通过 N 端亮氨酸丰富重复蛋白 3（NLRP3）炎性小体引发肺部炎症。然而，GF 引发炎症的分子靶点和机制仍不清楚。在这项研究中，我们鉴定出线粒体Src 家族激酶（mSFKs）是 GF 诱导的 NLRP3 炎性小体激活的关键决定因素。对 TKI 的综合分析表明，我们测试的所有 TKI 均可作为人单核细胞 THP-1 细胞和骨髓来源的巨噬细胞中 NLRP3 炎性小体的有效激动剂发挥作用。此外，这些 TKI 具有针对 mSFKs（如 c-Src、Fgr 和 Fyn）的共同非靶点活性。有趣的是，每种激酶的缺失都会自发刺激 THP-1 细胞中 NLRP3 炎性小体的激活。这些结果共同表明，NLRP3 感知 mSFKs 的活性降低，这是线粒体功能障碍的原因。因此，我们的研究结果表明 NLRP3 炎性小体和 mSFKs 之间存在机制联系，这为 NLRP3 炎性小体的新分子基础和细胞功能提供了新的认识。