Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE).
Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE).
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DOI：
10.1016/j.jconrel.2021.12.027
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Muzykantov VR
中科院分区：
文献类型：
--
作者：
Parhiz H;Brenner JS;Patel PN;Papp TE;Shahnawaz H;Li Q;Shi R;Zamora ME;Yadegari A;Marcos-Contreras OA;Natesan A;Pardi N;Shuvaev VV;Kiseleva R;Myerson JW;Uhler T;Riley RS;Han X;Mitchell MJ;Lam K;Heyes J;Weissman D;Muzykantov VR
目前的核苷修饰的RNA脂质纳米粒（modmRNA-LNP）技术已成功为COVID-19大流行期间下一代SARS-CoV-2疫苗的最高临床疗效数据铺平了道路。然而，这种modmRNA-LNP技术尚未在常见的预先存在的炎性或免疫激发的病症中表征，当在这种情况下施用modmRNA-LNP时，增加了不良临床作用的风险。在此，我们在小鼠中用脂多糖（LPS）经气管内（IT）（1 mg kg−1）或静脉内（IV）（2 mg kg−1）诱导急性炎症模型，然后在4小时后IV给予modmRNA-LNP（0.32 mg kg−1），并筛选炎性标志物，如促炎细胞因子。该剂量的ModmRNA-LNP在未处理小鼠中未引起细胞因子水平的显著升高。相反，在LPS免疫刺激后不久，modmRNA-LNP显著增强炎性细胞因子应答，血清中的白细胞介素-6（IL-6）和肝脏中的巨噬细胞炎性蛋白2（MIP-2）。我们的报告将这种现象确定为炎症加重（IE），这被证明是LNP特有的，不依赖于mRNA货物，并且被证明是时间和剂量依赖性的。巨噬细胞耗竭以及TLR 3 −/−和TLR 4 −/−敲除小鼠研究表明，巨噬细胞是参与或负责IE的免疫细胞。最后，我们表明，抗炎药物，如皮质类固醇，预处理可以部分减轻IE反应的小鼠。我们的发现表征了LNP介导的IE现象在革兰氏阴性细菌炎症中的重要性，然而，需要解决modmRNA-LNP在其他形式的慢性或急性炎症和免疫环境中的普遍性。
Current nucleoside-modified RNA lipid nanoparticle (modmRNA-LNP) technology has successfully paved the way for the highest clinical efficacy data from next-generation vaccinations against SARS-CoV-2 during the COVID-19 pandemic. However, such modmRNA-LNP technology has not been characterized in common pre-existing inflammatory or immune-challenged conditions, raising the risk of adverse clinical effects when administering modmRNA-LNPs in such cases. Herein, we induce an acute-inflammation model in mice with lipopolysaccharide (LPS) intratracheally (IT), 1 mg kg−1, or intravenously (IV), 2 mg kg−1, and then IV administer modmRNA-LNP, 0.32 mg kg−1, after 4 h, and screen for inflammatory markers, such as pro-inflammatory cytokines. ModmRNA-LNP at this dose caused no significant elevation of cytokine levels in naive mice. In contrast, shortly after LPS immune stimulation, modmRNA-LNP enhanced inflammatory cytokine responses, Interleukin-6 (IL-6) in serum and Macrophage Inflammatory Protein 2 (MIP-2) in liver significantly. Our report identifies this phenomenon as inflammation exacerbation (IE), which was proven to be specific to the LNP, acting independent of mRNA cargo, and was demonstrated to be time- and dose-dependent. Macrophage depletion as well as TLR3 −/− and TLR4−/− knockout mouse studies revealed macrophages were the immune cells involved or responsible for IE. Finally, we show that pretreatment with anti-inflammatory drugs, such as corticosteroids, can partially alleviate IE response in mice. Our findings characterize the importance of LNP-mediated IE phenomena in gram negative bacterial inflammation, however, the generalizability of modmRNA-LNP in other forms of chronic or acute inflammatory and immune contexts needs to be addressed.
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影响因子：
3.7
作者：
Ferrer MC;Shuvaev VV;Zern BJ;Composto RJ;Muzykantov VR;Eckmann DM
通讯作者：
Eckmann DM
DOI：
10.1016/j.jconrel.2013.09.013
发表时间：
2013-12-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Ernsting MJ;Murakami M;Roy A;Li SD
通讯作者：
Li SD
影响因子：
15
作者：
Chen, Delai;Love, Kevin T.;Anderson, Daniel G.
通讯作者：
Anderson, Daniel G.
影响因子：
12.4
作者：
Abrams, Marc T.;Koser, Martin L.;Sepp-Lorenzino, Laura
通讯作者：
Sepp-Lorenzino, Laura
影响因子：
16.6
作者：
Jayaraman, Muthusamy;Ansell, Steven M.;Mui, Barbara L.;Tam, Ying K.;Chen, Jianxin;Du, Xinyao;Butler, David;Eltepu, Laxman;Matsuda, Shigeo;Narayanannair, Jayaprakash K.;Rajeev, Kallanthottathil G.;Hafez, Ismail M.;Akinc, Akin;Maier, Martin A.;Tracy, Mark A.;Cullis, Pieter R.;Madden, Thomas D.;Manoharan, Muthiah;Hope, Michael J.
通讯作者：
Hope, Michael J.