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LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation
The Journal of Clinical Investigation ( IF 13.3 ) Pub Date : 2022 , DOI: 10.1172/jci153157
Jamie A Moore 1 , Jayna J Mistry 1, 2 , Charlotte Hellmich 1, 3 , Rebecca H Horton 1 , Edyta E Wojtowicz 1, 2 , Aisha Jibril 1 , Matthew Jefferson 1 , Thomas Wileman 1, 4 , Naiara Beraza 4 , Kristian M Bowles 1, 3 , Stuart A Rushworth 1
Affiliation  

The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation, and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for remaining apoptotic debris in regulating the immunologic response to and growth of solid tumors. Here, we investigated the role of macrophage LC3–associated phagocytosis (LAP) within the BM microenvironment of AML. Depletion of BM macrophages (BMMs) increased AML growth in vivo. We show that LAP is the predominate method of BMM phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to the accumulation of apoptotic cells (ACs) and apoptotic bodies (ABs), resulting in accelerated leukemia growth. Mechanistically, LAP of AML-derived ABs by BMMs resulted in stimulator of IFN genes (STING) pathway activation. We found that AML-derived mitochondrial damage–associated molecular patterns were processed by BMMs via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML-derived ABs showed that it was this mtDNA that was responsible for the induction of STING signaling in BMMs. Phenotypically, we found that STING activation suppressed AML growth through a mechanism related to increased phagocytosis. In summary, we report that macrophage LAP of apoptotic debris in the AML BM microenvironment suppressed tumor growth.

中文翻译:

骨髓巨噬细胞中 LC3 相关的吞噬作用通过 STING 激活抑制急性髓性白血病的进展

骨髓 (BM) 微环境调节急性髓性白血病 (AML) 的起始、增殖和化疗耐药性。在癌细胞死亡后,越来越多的证据表明,剩余的凋亡碎片在调节对实体瘤的免疫反应和生长方面发挥着重要作用。在这里,我们研究了巨噬细胞 LC3 相关吞噬作用 (LAP) 在 AML BM 微环境中的作用。BM 巨噬细胞 (BMM) 的消耗增加了体内 AML 的生长。我们表明,LAP 是 BMM 吞噬 AML 微环境中死亡和垂死细胞的主要方法。LAP 的靶向抑制导致凋亡细胞 (ACs) 和凋亡小体 (ABs) 的积累,导致白血病加速生长。机械地,BMM 对 AML 衍生 AB 的 LAP 导致 IFN 基因刺激因子 (STING) 通路激活。我们发现 AML 衍生的线粒体损伤相关分子模式由 BMM 通过 LAP 处理。此外,AML 衍生的 AB 中线粒体 DNA (mtDNA) 的消耗表明,正是这种 mtDNA 负责在 BMM 中诱导 STING 信号传导。在表型上,我们发现 STING 激活通过与吞噬作用增加相关的机制抑制 AML 生长。总之,我们报告了 AML BM 微环境中凋亡碎片的巨噬细胞 LAP 抑制了肿瘤生长。AML 衍生的 AB 中线粒体 DNA (mtDNA) 的消耗表明,正是这种 mtDNA 负责在 BMM 中诱导 STING 信号传导。在表型上,我们发现 STING 激活通过与吞噬作用增加相关的机制抑制 AML 生长。总之,我们报告了 AML BM 微环境中凋亡碎片的巨噬细胞 LAP 抑制了肿瘤生长。AML 衍生的 AB 中线粒体 DNA (mtDNA) 的消耗表明,正是这种 mtDNA 负责在 BMM 中诱导 STING 信号传导。在表型上,我们发现 STING 激活通过与吞噬作用增加相关的机制抑制 AML 生长。总之,我们报告了 AML BM 微环境中凋亡碎片的巨噬细胞 LAP 抑制了肿瘤生长。
更新日期:2022-03-01
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