线粒体DNA经STING信号通路介导免疫应答的研究进展
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摘要
近期研究显示,线粒体的功能已不单单限于有氧呼吸及能量合成,线粒体释放的损伤相关分子模式(尤其是线粒体DNA)参与机体的一系列免疫调控,介导机体特定免疫应答的形成与发展。近年新发现的循环鸟苷酸-腺苷酸合成酶(cGAS-STING)信号通路不仅负责识别外源性致病菌DNA,同样识别内源性DNA(包括线粒体DNA)。干扰素基因刺激蛋白(STING)介导的线粒体DNA广泛参与机体多种炎性疾病、感染性疾病及肿瘤的发生发展。本文将概述STING识别线粒体DNA的分子通路,阐释线粒体DNA参与形成肿瘤免疫微环境的机制,着重讨论线粒体DNA诱导细胞凋亡、自噬及中性粒细胞陷阱形成的免疫学过程与临床意义。
Recent studies reveal that mitochondria plays not only as energy generator but also as immune participant. Mitochondrial DNA recognized by cGAS-STING signaling is involved in various infectious, inflammatory and tumorigenesis events. This review will summarize the molecular signaling of STING-mediated mitochondrial DNA during pathophysiological conditions, explain the mechanism by which mitochondrial DNA induces tumor microenvironment, and discuss how mitochondrial DNA participates in cell apoptosis, autophagy and neutrophil-induced traps.
Recent studies reveal that mitochondria plays not only as energy generator but also as immune participant. Mitochondrial DNA recognized by cGAS-STING signaling is involved in various infectious, inflammatory and tumorigenesis events. This review will summarize the molecular signaling of STING-mediated mitochondrial DNA during pathophysiological conditions, explain the mechanism by which mitochondrial DNA induces tumor microenvironment, and discuss how mitochondrial DNA participates in cell apoptosis, autophagy and neutrophil-induced traps.
引文
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[26] Liu X,Pu Y,Cron K,et al.CD47 blockade triggers T cell-mediated destruction of immunogenic tumors[J].Nat Med,2015,21(10):1209-1215.
[27] 刘颂,任建安.炎症性肠病中cGAS-cGAMP-STING识别病原体DNA的研究进展[J].国际外科学杂志,2015,42(7):493-497.
[28] Liu S,Feng M,Guan W.Mitochondrial DNA sensing by STING signaling participates in inflammation,cancer and beyond[J].Int J Cancer,2016,139(4):736-741.
[29] Rustom A,Saffrich R,Markovic I,et al.Nanotubular highways for intercellular organelle transport[J].Science,2004,303(5660):1007-1010.
[30] Rebbeck CA,Leroi AM,Burt A.Mitochondrial capture by a transmissible cancer[J].Science,2011,331(6015):303-303.
[31] Tan AS,Baty JW,Dong LF,et al.Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA[J].Cell Metab,2015,21(1):81-94.
[32] Pasquier J,Guerrouahen BS,Al Thawadi H,et al.Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance[J].J Transl Med,2013,11:94-94.
[33] 刘颂,任建安.炎症性肠病中肠道树突状细胞经cGAS-cGAMP-STING识别病原体DNA的机制研究进展[J].国际外科学杂志,2015,42(7):493-497.
[2] Hemmi H,Takeuchi O,Kawai T,et al.A toll-like receptor recognizes bacterial DNA[J].Nature,2000,408(6813):740-745.
[3] Liu S,Zhang Y,Ren J,et al.Microbial DNA recognition by cGAS-STING and other sensors in dendritic cells in inflammatory bowel diseases[J].Inflamm Bowel Dis,2015,21(4):901-911.
[4] Sun L,Wu J,Du F,et al.Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway[J].Science,2013,339(6121):786-791.
[5] Abe T,Barber GN.Cytosolic-DNA-mediated,STING-dependent proinflammatory gene induction necessitates canonical NF-kappaB activation through TBK1[J].J Virol,2014,88(10):5328-5341.
[6] Ishikawa H,Barber GN.STING is an endoplasmic reticulum adaptor that facilitates innate immune signaling[J].Nature,2008,455(7213):674-678.
[7] McWhirter SM,Barbalat R,Monroe KM,et al.A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP[J].J Exp Med,2009,206(9):1899-1911.
[8] Rongvaux A,Jackson R,Harman CC,et al.Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA[J].Cell,2014,159(7):1563-1577.
[9] White MJ,McArthur K,Metcalf D,et al.Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production[J].Cell,2014,159(7):1549-1562.
[10] West AP,Khoury-Hanold W,Staron M,et al.Mitochondrial DNA stress primes the antiviral innate immune response[J].Nature,2015,520(7548):553-557.
[11] Yousefi S,Gold JA,Andina N,et al.Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense[J].Nat Med,2008,14(9):949-953.
[12] Collins LV,Hajizadeh S,Holme E,et al.Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses[J].J Leukoc Biol,2004,75(6):995-1000.
[13] Brinkmann V,Reichard U,Goosmann C,et al.Neutrophil extracellular traps kill bacteria[J].Science,2004,303(5663):1532-1535.
[14] Yousefi S,Mihalache C,Kozlowski E,et al.Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps[J].Cell Death Differ,2009,16(11):1438-1444.
[15] McIlroy DJ,Jarnicki AG,Au GG,et al.Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery[J].J Crit Care,2014,29(6):1133.e1-1133.e5.
[16] Zhang Q,Raoof M,Chen Y,et al.Circulating mitochondrial DAMPs cause inflammatory responses to injury[J].Nature,2010,464(7285):104-107.
[17] Itagaki K,Kaczmarek E,Lee YT,et al.Mitochondrial DNA released by trauma induces neutrophil extracellular traps[J].PLoS One,2015,10(3):e0120549- e0120549.
[18] Petrasek J,Iracheta-Vellve A,Csak T,et al.STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease[J].Proc Natl Acad Sci U S A,2013,110(41):16544-16549.
[19] Liu Y,Jesus AA,Marrero B,et al.Activated STING in a vascular and pulmonary syndrome[J].N Engl J Med,2014,371(6):507-518.
[20] Watson RO,Manzanillo PS,Cox JS.Extracellular M.tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway[J].Cell,2012,150(4):803-815.
[21] Watson RO,Bell SL,MacDuff DA,et al.The cytosolic sensor cGAS detects Mycobacterium tuberculosis DNA to induce type I interferons and activate autophagy[J].Cell Host Microbe,2015,17(6):811-819.
[22] Wassermann R,Gulen MF,Sala C,et al.Mycobacterium tuberculosis differentially activates cGAS- and inflammasome-dependent intracellular immune responses through ESX-1[J].Cell Host Microbe,2015,17(6):799-810.
[23] Collins AC,Cai H,Li T,et al.Cyclic GMP-AMP synthase is an innate immune DNA sensor for Mycobacterium tuberculosis[J].Cell Host Microbe,2015,17(6):820-828.
[24] Liang Q,Seo GJ,Choi YJ,et al.Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses[J].Cell Host Microbe,2014,15(2):228-238.
[25] Timmermans K,Kox M,Gerretsen J,et al.The involvement of danger-associated molecular patterns in the development of immunoparalysis in cardiac arrest patients[J].Crit Care Med,2015,43(11):2332-2338.
[26] Liu X,Pu Y,Cron K,et al.CD47 blockade triggers T cell-mediated destruction of immunogenic tumors[J].Nat Med,2015,21(10):1209-1215.
[27] 刘颂,任建安.炎症性肠病中cGAS-cGAMP-STING识别病原体DNA的研究进展[J].国际外科学杂志,2015,42(7):493-497.
[28] Liu S,Feng M,Guan W.Mitochondrial DNA sensing by STING signaling participates in inflammation,cancer and beyond[J].Int J Cancer,2016,139(4):736-741.
[29] Rustom A,Saffrich R,Markovic I,et al.Nanotubular highways for intercellular organelle transport[J].Science,2004,303(5660):1007-1010.
[30] Rebbeck CA,Leroi AM,Burt A.Mitochondrial capture by a transmissible cancer[J].Science,2011,331(6015):303-303.
[31] Tan AS,Baty JW,Dong LF,et al.Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA[J].Cell Metab,2015,21(1):81-94.
[32] Pasquier J,Guerrouahen BS,Al Thawadi H,et al.Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance[J].J Transl Med,2013,11:94-94.
[33] 刘颂,任建安.炎症性肠病中肠道树突状细胞经cGAS-cGAMP-STING识别病原体DNA的机制研究进展[J].国际外科学杂志,2015,42(7):493-497.