美国威尔康奈尔医学院Virginia Pascual等研究人员合作发现，I型干扰素驱动狼疮单核细胞中非经典IL-1β的分泌。该研究于2024年10月7日在线发表于国际一流学术期刊《免疫》。

研究人员表示，保留线粒体的红细胞（Mito⁺ RBC）的调理作用是系统性红斑狼疮（SLE）的特征，可触发巨噬细胞中I型干扰素（IFN）的产生。

研究人员报道了单核细胞（Mos）在Mito⁺ RBC调理作用后共同产生IFN和成熟的白细胞介素-1β（mIL-1β）。IFN的表达依赖于环磷酸鸟苷-AMP合成酶（cGAS）和RIG-I样受体（RLR）对Mito⁺ RBC来源的线粒体DNA（mtDNA）和mtRNA的感应。白细胞介素-1β（IL-1β）的产生由RLR抗病毒信号适配器（MAVS）通路识别Mito⁺ RBC来源的mtRNA所启动。这导致了单核细胞mtDNA的细胞质释放，进而激活了炎症小体。

重要的是，mIL-1β的分泌不依赖于gasdermin D（GSDMD）和焦亡，但依赖于IFN诱导的抗病毒蛋白1（MxA），后者促进了mIL-1β进入转高尔基体（TGN）介导的分泌途径。红细胞的内吞作用识别出一部分表达IFN刺激基因（ISG）的血液单核细胞，这些细胞释放mIL-1β，并在活跃疾病的SLE患者中扩增。

附：英文原文

Title: Type I IFN drives unconventional IL-1β secretion in lupus monocytes

Author: Simone Caielli, Preetha Balasubramanian, Juan Rodriguez-Alcazar, Uthra Balaji, Lauren Robinson, Zurong Wan, Jeanine Baisch, Cynthia Smitherman, Lynnette Walters, Paola Sparagana, Djamel Nehar-Belaid, Radu Marches, Lorien Nassi, Katie Stewart, Julie Fuller, Jacques F. Banchereau, Jinghua Gu, Tracey Wright, Virginia Pascual

Issue&Volume: 2024-10-07

Abstract: 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.

DOI: 10.1016/j.immuni.2024.09.004

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00448-5