Caielli Simone, Balasubramanian Preetha, Rodriguez-Alcazar Juan, Balaji Uthra, Wan Zurong, Baisch Jeanine, Smitherman Cynthia, Walters Lynnette, Sparagana Paola, Nehar-Belaid Djamel, Marches Radu, Nassi Lorien, Stewart Katie, Fuller Julie, Banchereau Jacques F, Gu Jinghua, Wright Tracey, Pascual Virginia
bioRxiv. 2023 Aug 3:2023.08.03.551696. doi: 10.1101/2023.08.03.551696.
Systemic Lupus Erythematosus (SLE) is characterized by autoreactive B cell activation, upregulation of Type I Interferon (IFN) and widespread inflammation. Mitochondrial nucleic acids (NAs) are increasingly recognized as triggers of IFN . Thus, defective removal of mitochondria from mature red blood cells (Mito RBCs), a feature of SLE, contributes to IFN production by myeloid cells . Here we identify blood monocytes (Mo) that have internalized RBCs and co-express IFN-stimulated genes (ISGs) and interleukin-1β (IL-1β) in SLE patients with active disease. We show that ISG expression requires the interaction between Mito RBC-derived mitochondrial DNA (mtDNA) and cGAS, while IL-1β production entails Mito RBC-derived mitochondrial RNA (mtRNA) triggering of RIG-I-like receptors (RLRs). This leads to the cytosolic release of Mo-derived mtDNA that activates the NLRP3 inflammasome. Importantly, IL-1β release depends on the IFN-inducible myxovirus resistant protein 1 (MxA), which enables the translocation of this cytokine into a trans-Golgi network (TGN)-mediated unconventional secretory pathway. Our study highlights a novel and synergistic pathway involving IFN and the NLRP3 inflammasome in SLE.
系统性红斑狼疮（SLE）的特征是自身反应性B细胞活化、I型干扰素（IFN）上调和广泛炎症。线粒体核酸（NAs）越来越被认为是IFN的触发因素。因此，成熟红细胞（Mito RBCs）中线粒体清除缺陷是SLE的一个特征，它有助于髓样细胞产生IFN。在这里，我们鉴定出在活动性疾病的SLE患者中内化了红细胞并共表达IFN刺激基因（ISGs）和白细胞介素-1β（IL-1β）的血液单核细胞（Mo）。我们表明，ISG表达需要Mito RBC衍生的线粒体DNA（mtDNA）与cGAS之间的相互作用，而IL-1β的产生需要Mito RBC衍生的线粒体RNA（mtRNA）触发RIG-I样受体（RLRs）。这导致Mo衍生的mtDNA的胞质释放，从而激活NLRP3炎性小体。重要的是，IL-1β的释放依赖于IFN诱导的抗黏液病毒蛋白1（MxA），它使这种细胞因子能够转运到反式高尔基体网络（TGN）介导的非常规分泌途径中。我们的研究突出了SLE中涉及IFN和NLRP3炎性小体的一种新的协同途径。
