O'Siorain James R, Cox Shannon L, Payet Cloé, Nally Frances K, He Yan, Drewinksi Tabea T, Kennedy Oran D, Dowling Jennifer K, Mellett Mark, Early James O, Curtis Annie M
Curtis Clock Laboratory, School of Pharmacy and Biomolecular Sciences (PBS), Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, China.
FASEB J. 2024 Dec 13;38(24):e70235. doi: 10.1096/fj.202400508RR.
Macrophages are innate immune cells that orchestrate the process of inflammation, which varies across time of day. This ensures appropriate biological timing of the immune response with the external environment. The NLRP3 inflammasome mediates IL-1-family cytokine release via pyroptosis. Mitochondria play a multifaceted role regulating NLRP3 inflammasome activity. Mitochondria exhibit distinct metabolic changes across time of day, which are influenced by clock genes. However, whether the macrophage clock regulates the NLRP3 inflammasome via mitochondrial control remains unclear. We find heightened mitochondrial membrane potential (Δψm) and enhanced NLRP3 inflammasome activation from peritoneal exudate cells (PECs) isolated at circadian time (CT) 12 compared to CT 0. In vitro time-of-day synchronization of bone-marrow derived macrophages (BMDMs) induced time-dependent differences in NLRP3 inflammasome activation. Myeloid-specific Bmal1-deletion enhanced NLRP3 inflammasome activity in PECs at CT0 and in unsynchronized BMDMs compared to controls. Pharmacologically disrupting Δψm in synchronized cells reduced NLRP3 inflammasome activation to comparable levels, and the same occurred with Bmal1-deletion. These results further demonstrate circadian clock timing of the NLRP3 inflammasome, which is dependent on mitochondrial function and driven through the circadian gene Bmal1.
巨噬细胞是协调炎症过程的固有免疫细胞，炎症过程会随一天中的时间而变化。这确保了免疫反应与外部环境的适当生物时间同步。NLRP3炎性小体通过细胞焦亡介导白细胞介素-1家族细胞因子的释放。线粒体在调节NLRP3炎性小体活性方面发挥多方面作用。线粒体在一天中的不同时间表现出明显的代谢变化，这受到生物钟基因的影响。然而，巨噬细胞生物钟是否通过线粒体控制来调节NLRP3炎性小体仍不清楚。我们发现，与CT0相比，在昼夜时间（CT）12分离的腹腔渗出细胞（PEC）中线粒体膜电位（Δψm）升高，NLRP3炎性小体激活增强。体外对骨髓来源的巨噬细胞（BMDM）进行一天中的时间同步，诱导了NLRP3炎性小体激活的时间依赖性差异。与对照组相比，髓系特异性Bmal1缺失增强了CT0时PEC和未同步的BMDM中NLRP3炎性小体的活性。在同步细胞中通过药物破坏Δψm可将NLRP3炎性小体激活降低到可比水平，Bmal1缺失时也会出现同样情况。这些结果进一步证明了NLRP3炎性小体的昼夜节律时钟定时，其依赖于线粒体功能并由昼夜节律基因Bmal1驱动。
