Myeloid autophagy genes protect mice against fatal TNF- and LPS-induced cytokine storm syndromes.
Myeloid autophagy genes protect mice against fatal TNF- and LPS-induced cytokine storm syndromes.
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DOI：
10.1080/15548627.2022.2116675
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发表时间：
2023-04
期刊：
影响因子：
13.3
通讯作者：
Orvedahl, Anthony
中科院分区：
文献类型：
--
作者：
Wang, Ya-Ting;Sansone, Amy;Smirnov, Asya;Stallings, Christina L.;Orvedahl, Anthony
巨自噬/自噬通过多种机制调节炎症，包括特定细胞组分的溶酶体降解。某些自噬基因“盒”也参与非规范过程以介导重要的生物活性。虽然骨髓细胞中的选择性自噬基因与保护细胞因子风暴综合征（CSS）模型中的小鼠有关，但迄今为止尚未报道对这种疾病的自噬途径进行更广泛的遗传分析。我们确定，髓腔中的多个典型自噬基因可保护免受静脉内TNF和腹膜内LPS的致命疾病，但值得注意的是，Atg 14对后者是无效的。血清细胞因子分析和遗传杂交进一步揭示了不同的机制有助于这些CSS模型中自噬基因缺陷小鼠的超敏反应。令人惊讶的是，TNF与用LPS攻击的髓系5缺陷小鼠的死亡率增加无关。在表达ITGAX/CD 11 c和LYZ 2/LYSM但不表达S100 A8/MRP 8的细胞中，Atg 5的组织特异性消融定义了一个骨髓亚群，该亚群可保护免受TNF的影响，而在表达LYZ 2的细胞的不同亚群中，Atg 5可保护免受LPS的影响。总之，这项研究确定了自噬基因组和特定的细胞类型，这些基因组和细胞类型可以防止CSS引起的致命炎症，突出了两种常用的小鼠模型的重要差异。ATG 5：自噬相关5; ATG 7：自噬相关7; ATG 14：自噬相关14; ATG 16 L1：自噬相关16样1（S. cerevisiae）; BECN 1：beclin 1，自噬相关; CASP 1：胱天蛋白酶1; CASP 4/CASP 11：胱天蛋白酶4，凋亡相关半胱氨酸肽酶; CIM：条件永生化巨噬细胞; CLP：盲肠结扎和穿刺; CSS：细胞因子风暴综合征; DC：树突状细胞; IFNG/IFNγ：干扰素γ; IFNGR 1：干扰素γ受体1; ip：腹膜内; iv：静脉内; IL 12/p70：白细胞介素12，p70异二聚体; IL18：白细胞介素18; ITGAX/CD11c：整合素α X;：LC 3相关吞噬作用;脂多糖：脂多糖; LYZ2/LYSM：溶菌酶2; MAP1LC 3A/LC 3：微管相关蛋白1轻链3 α; RB 1CC 1/FIP 200：RB 1诱导卷曲螺旋1; S100 A8/MRP 8：S100钙结合蛋白A8（钙颗粒蛋白A）; TICAM 1/TRIF：含TIR结构域的衔接分子1; TLR 4：toll样受体4; TNF：肿瘤坏死因子。
Macroautophagy/autophagy regulates inflammation via multiple mechanisms, including lysosomal degradation of specific cellular components. Certain autophagy gene “cassettes” also participate in non-canonical processes to mediate important biological activities. While select autophagy genes in myeloid cells have been implicated in protecting mice in models of cytokine storm syndromes (CSS), a more extensive genetic analysis of the autophagy pathway for this disorder has not been reported to date. We determined that multiple canonical autophagy genes in the myeloid compartment protected against fatal disease from both intravenous TNF and intraperitoneal LPS, with the notable exception that Atg14 was dispensable for the latter. Serum cytokine analyses and genetic crosses further revealed distinct mechanisms contribute to the hypersensitivity of autophagy gene-deficient mice in these CSS models. Surprisingly, TNF was dispensable for the increased mortality of myeloid 5-deficient mice challenged with LPS. Tissue-specific ablation of Atg5 in cells expressing ITGAX/CD11c and LYZ2/LYSM, but not S100A8/MRP8, defined a myeloid subset that protected against TNF, while protection against LPS was conferred by Atg5 in a distinct subset of LYZ2-expressing cells. Together, this study identifies autophagy gene sets and specific cell types that protect against fatal inflammation due to CSS, highlighting important differences in two commonly used murine models of the disorder. ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CASP1: caspase 1; CASP4/CASP11: caspase 4, apoptosis-related cysteine peptidase; CIM: conditionally immortalized macrophage; CLP: cecal ligation and puncture; CSS: cytokine storm syndrome; DC: dendritic cell; IFNG/IFNγ: interferon gamma; IFNGR1: interferon gamma receptor 1; ip: intraperitoneal; iv: intravenous; IL12/p70: interleukin 12, p70 heterodimer; IL18: Interleukin 18; ITGAX/CD11c: integrin alpha X; LAP: LC3-associated phagocytosis; LPS: lipopolysaccharide; LYZ2/LYSM: lysozyme 2; MAP1LC3A/LC3: microtubule-associated protein 1 light chain 3 alpha; RB1CC1/FIP200: RB1-inducible coiled-coil 1; S100A8/MRP8: S100 calcium binding protein A8 (calgranulin A); TICAM1/TRIF: TIR domain containing adaptor molecule 1; TLR4: toll-like receptor 4; TNF: tumor necrosis factor.
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影响因子：
64.8
作者：
Diao, Jiajie;Liu, Rong;Rong, Yueguang;Zhao, Minglei;Zhang, Jing;Lai, Ying;Zhou, Qiangjun;Wilz, Livia M.;Li, Jianxu;Vivona, Sandro;Pfuetzner, Richard A.;Brunger, Axel T.;Zhong, Qing
通讯作者：
Zhong, Qing
影响因子：
10.5
作者：
Chen S;Wang C;Yeo S;Liang CC;Okamoto T;Sun S;Wen J;Guan JL
通讯作者：
Guan JL
DOI：
10.1084/jem.171.6.1853
发表时间：
1990-06-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Heremans H;Van Damme J;Dillen C;Dijkmans R;Billiau A
通讯作者：
Billiau A
DOI：
10.4049/jimmunol.1402277
发表时间：
2015-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Abdel Fattah E;Bhattacharya A;Herron A;Safdar Z;Eissa NT
通讯作者：
Eissa NT
DOI：
10.1038/nri.2016.100
发表时间：
2016-11
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Cadwell K
通讯作者：
Cadwell K