线粒体核酸激活先天性免疫的机制和影响

IF 4.8 4区 医学 Q2 IMMUNOLOGY International immunology Pub Date : 2024-08-30 DOI:10.1093/intimm/dxae052
Prashant Rai, Michael B Fessler
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引用次数: 0

摘要

近年来,线粒体在先天性免疫中发挥的作用越来越多。其中一个主要机制是,线粒体核酸物种在应对一系列微生物和非微生物环境压力时从线粒体基质转位到细胞膜和溶酶体内腔,被认为是先天性免疫反应细胞信号传递过程中的第二信使事件。因此,线粒体 DNA 和 RNA 已被证明可通过涉及线粒体内外膜重塑的多种调节机制进入细胞膜,并通过囊泡运输进入溶酶体,从而激活细胞膜(如环状 GMP-AMP 合成酶)、环 GMP-AMP 合成酶 [cGAS];视黄酸诱导基因-I [RIG-I]样受体)和溶酶体内(Toll 样受体 [TLR]7, -9)核酸受体,从而诱导 I 型干扰素和促炎细胞因子。在这篇微型综述中,我们将讨论线粒体核酸错位的分子机制及其在宿主防御、自身免疫和自身炎症性疾病中的作用。新出现的模式是,宿主衍生 DNA 在先天性免疫反应中有趣地充当了信号放大器,同时也是细胞器平衡紊乱的警报信号。因此,每个细胞中明显过量的线粒体和线粒体 DNA 核苷酸可能会使细胞对应激反应更加敏感,同时确保完整线粒体的基本储备,以维持细胞的新陈代谢。对这些分子机制的进一步了解有望为未来干预人类疾病的治疗提供机会。
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Mechanisms and Effects of Activation of Innate Immunity by Mitochondrial Nucleic Acids.

In recent years, a growing number of roles have been identified for mitochondria in innate immunity. One principal mechanism is that translocation of mitochondrial nucleic acid species from the mitochondrial matrix to the cytosol and endolysosomal lumen in response to an array of microbial and non-microbial environmental stressors has been found to serve as a second messenger event in the cell signaling of the innate immune response. Thus, mitochondrial DNA and RNA have been shown to access the cytosol through several regulated mechanisms involving remodeling of the mitochondrial inner and outer membranes and to access lysosomes via vesicular transport, thereby activating cytosolic (e.g., cyclic GMP-AMP synthase [cGAS]; retinoic acid-inducible gene-I [RIG-I]-like receptors) and endolysosomal (Toll-like Receptor [TLR]7, -9) nucleic acid receptors that induce type I interferons and pro-inflammatory cytokines. In this mini-review, we discuss these molecular mechanisms of mitochondrial nucleic acid mislocalization and their roles in host defense, autoimmunity, and auto-inflammatory disorders. The emergent paradigm is one in which host-derived DNA interestingly serves as a signal amplifier in the innate immune response and also as an alarm signal for disturbances in organellar homeostasis. The apparent vast excess of mitochondria and mitochondrial DNA nucleoids per cell may thus serve to sensitize the cell response to stressors while ensuring an underlying reserve of intact mitochondria to sustain cellular metabolism. An improved understanding of these molecular mechanisms will hopefully afford future opportunities for therapeutic intervention in human disease.

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来源期刊
International immunology
International immunology 医学-免疫学
CiteScore
9.30
自引率
2.30%
发文量
51
审稿时长
6-12 weeks
期刊介绍: International Immunology is an online only (from Jan 2018) journal that publishes basic research and clinical studies from all areas of immunology and includes research conducted in laboratories throughout the world.
期刊最新文献
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