Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression.
Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression.
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DOI：
10.1038/s41467-018-07305-8
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发表时间：
2018-12-03
影响因子：
16.6
通讯作者：
Bellone M
中科院分区：
文献类型：
--
作者：
Calcinotto A;Brevi A;Chesi M;Ferrarese R;Garcia Perez L;Grioni M;Kumar S;Garbitt VM;Sharik ME;Henderson KJ;Tonon G;Tomura M;Miwa Y;Esplugues E;Flavell RA;Huber S;Canducci F;Rajkumar VS;Bergsagel PL;Bellone M
肠道微生物区系与癌症有因果关系，但肠道微生物如何影响粘膜外肿瘤的进展尚不清楚。在这里，我们提供的证据表明，普氏肝素促进Th17细胞在肠道定植并迁移到转基因VK*MYC小鼠的骨髓(BM)的分化，在那里他们有利于多发性骨髓瘤(MM)的进展。VK*MYC小鼠体内缺乏IL-17或其微生物群落紊乱延迟了MM的出现。同样，在阴郁的多发性骨髓瘤患者中，骨髓IL-17水平较高预示着疾病进展更快。IL-17诱导小鼠浆细胞STAT3磷酸化，并激活嗜酸性粒细胞。用阻断IL-17、IL-17RA和IL-5的抗体治疗VK*MYC小鼠可减少Th17细胞和嗜酸性粒细胞的骨髓积聚，延缓疾病进展。因此，在VK*MYC小鼠中，共生细菌似乎释放了适应性免疫和先天免疫之间的旁分泌信号网络，加速了MM的进展，并可以成为现有治疗方法的靶点。肠道微生物区系影响粘膜外肿瘤的机制尚不清楚。在这里，作者表明，肠道微生物区系通过诱导骨髓中Th17细胞的分化和迁移来促进多发性骨髓瘤，从而也增加了促肿瘤嗜酸性粒细胞的招募。
The gut microbiota has been causally linked to cancer, yet how intestinal microbes influence progression of extramucosal tumors is poorly understood. Here we provide evidence implying that Prevotella heparinolytica promotes the differentiation of Th17 cells colonizing the gut and migrating to the bone marrow (BM) of transgenic Vk*MYC mice, where they favor progression of multiple myeloma (MM). Lack of IL-17 in Vk*MYC mice, or disturbance of their microbiome delayed MM appearance. Similarly, in smoldering MM patients, higher levels of BM IL-17 predicted faster disease progression. IL-17 induced STAT3 phosphorylation in murine plasma cells, and activated eosinophils. Treatment of Vk*MYC mice with antibodies blocking IL-17, IL-17RA, and IL-5 reduced BM accumulation of Th17 cells and eosinophils and delayed disease progression. Thus, in Vk*MYC mice, commensal bacteria appear to unleash a paracrine signaling network between adaptive and innate immunity that accelerates progression to MM, and can be targeted by already available therapies. The mechanisms through which gut microbiota affect extramucosal tumors are poorly understood. Here the authors show that the gut microbiota promotes multiple myeloma by inducing differentiation and migration of Th17 cells in the bone marrow resulting also in increased recruitment of pro-tumorigenic eosinophils.
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影响因子：
82.9
作者：
Chesi M;Mirza NN;Garbitt VM;Sharik ME;Dueck AC;Asmann YW;Akhmetzyanova I;Kosiorek HE;Calcinotto A;Riggs DL;Keane N;Ahmann GJ;Morrison KM;Fonseca R;Lacy MQ;Dingli D;Kumar SK;Ailawadhi S;Dispenzieri A;Buadi F;Gertz MA;Reeder CB;Lin Y;Chanan-Khan AA;Stewart AK;Fooksman D;Bergsagel PL
通讯作者：
Bergsagel PL
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
7.2
作者：
Calcinotto, Arianna;Ponzoni, Maurilio;Bellone, Matteo
通讯作者：
Bellone, Matteo
影响因子：
64.8
作者：
Grivennikov, Sergei I.;Wang, Kepeng;Mucida, Daniel;Stewart, C. Andrew;Schnabl, Bernd;Jauch, Dominik;Taniguchi, Koji;Yu, Guann-Yi;Oesterreicher, Christoph H.;Hung, Kenneth E.;Datz, Christian;Feng, Ying;Fearon, Eric R.;Oukka, Mohamed;Tessarollo, Lino;Coppola, Vincenzo;Yarovinsky, Felix;Cheroutre, Hilde;Eckmann, Lars;Trinchieri, Giorgio;Karin, Michael
通讯作者：
Karin, Michael
影响因子：
30.3
作者：
Ivanov II;Honda K
通讯作者：
Honda K