Drukier Institute for Children's Health, Weill Cornell Medicine, New York, NY, USA; Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
Drukier Institute for Children's Health, Weill Cornell Medicine, New York, NY, USA; Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
Immunity. 2024 Nov 12;57(11):2497-2513.e12. doi: 10.1016/j.immuni.2024.09.004. Epub 2024 Oct 7.
Opsonization of red blood cells that retain mitochondria (Mito RBCs), a feature of systemic lupus erythematosus (SLE), triggers type I interferon (IFN) production in macrophages. We report that monocytes (Mos) co-produce IFN and mature interleukin-1β (mIL-1β) upon Mito RBC opsonization. IFN expression depended on cyclic GMP-AMP synthase (cGAS) and RIG-I-like receptors' (RLRs) sensing of Mito RBC-derived mitochondrial DNA (mtDNA) and mtRNA, respectively. Interleukin-1β (IL-1β) production was initiated by the RLR antiviral signaling adaptor (MAVS) pathway recognition of Mito RBC-derived mtRNA. This led to the cytosolic release of Mo mtDNA, which activated the inflammasome. Importantly, mIL-1β secretion was independent of gasdermin D (GSDMD) and pyroptosis but relied on IFN-inducible myxovirus-resistant protein 1 (MxA), which facilitated the incorporation of mIL-1β into a trans-Golgi network (TGN)-mediated secretory pathway. RBC internalization identified a subset of blood Mo expressing IFN-stimulated genes (ISGs) that released mIL-1β and expanded in SLE patients with active disease.
红细胞被线粒体（Mito RBC）包裹，这是红斑狼疮（SLE）的一个特征，这种现象会触发巨噬细胞产生 I 型干扰素（IFN）。我们的研究报告表明，Mito RBC 被包裹后，单核细胞（Mos）会共同产生 IFN 和成熟的白细胞介素-1β（mIL-1β）。IFN 的表达取决于环鸟苷酸-腺苷酸合酶（cGAS）和 RIG-I 样受体（RLRs）分别识别 Mito RBC 衍生的线粒体 DNA（mtDNA）和 mtRNA。IL-1β 的产生是由 RLR 抗病毒信号衔接蛋白（MAVS）途径识别 Mito RBC 衍生的 mtRNA 引发的。这导致 Mo mtDNA 在细胞质中的释放，从而激活了炎症小体。重要的是，mIL-1β 的分泌不依赖于 gasdermin D（GSDMD）和细胞焦亡，但依赖于 IFN 诱导的抗黏液病毒蛋白 1（MxA），它促进了 mIL-1β 纳入经高尔基网络（TGN）介导的分泌途径。红细胞内吞作用鉴定出一组表达 IFN 刺激基因（ISGs）的血液 Mo，这些 Mo 会释放 mIL-1β，并在 SLE 患者中疾病活跃时扩张。
