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Expression of Free Fatty Acid Receptor 2 by Dendritic Cells Prevents Their Expression of Interleukin 27 and Is Required for Maintenance of Mucosal Barrier and Immune Response Against Colorectal Tumors in Mice.
Gastroenterology ( IF 25.7 ) Pub Date : 2020-01-07 , DOI: 10.1053/j.gastro.2019.12.027 Sydney Lavoie 1 , Eunyoung Chun 1 , Sena Bae 1 , Caitlin A Brennan 1 , Carey Ann Gallini Comeau 1 , Jessica K Lang 1 , Monia Michaud 1 , Hamid R Hoveyda 2 , Graeme L Fraser 3 , Miles H Fuller 4 , Brian T Layden 5 , Jonathan N Glickman 6 , Wendy S Garrett 7
Gastroenterology ( IF 25.7 ) Pub Date : 2020-01-07 , DOI: 10.1053/j.gastro.2019.12.027 Sydney Lavoie 1 , Eunyoung Chun 1 , Sena Bae 1 , Caitlin A Brennan 1 , Carey Ann Gallini Comeau 1 , Jessica K Lang 1 , Monia Michaud 1 , Hamid R Hoveyda 2 , Graeme L Fraser 3 , Miles H Fuller 4 , Brian T Layden 5 , Jonathan N Glickman 6 , Wendy S Garrett 7
Affiliation
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BACKGROUND & AIMS
Intestinal microbes and their metabolites affect the development of colorectal cancer (CRC). Short-chain fatty acids are metabolites generated by intestinal microbes from dietary fiber. We investigated the mechanisms by which free fatty acid receptor 2 (FFAR2), a receptor for short-chain fatty acids that can affect the composition of the intestinal microbiome, contributes to the pathogenesis of CRC.
METHODS
We performed studies with ApcMin/+ mice, ApcMin/+Ffar2-/- mice, mice with conditional disruption of Ffar2 in dendritic cells (DCs) (Ffar2fl/flCD11c-Cre mice), ApcMin/+Ffar2fl/flCD11c-Cre mice, and Ffar2fl/fl mice (controls); some mice were given dextran sodium sulfate to induce colitis, with or without a FFAR2 agonist or an antibody against interleukin 27 (IL27). Colon and tumor tissues were analyzed by histology, quantitative polymerase chain reaction, and 16S ribosomal RNA gene sequencing; lamina propria and mesenteric lymph node tissues were analyzed by RNA sequencing and flow cytometry. Intestinal permeability was measured after gavage with fluorescently labeled dextran. We collected data on colorectal tumors from The Cancer Genome Atlas.
RESULTS
ApcMin/+Ffar2-/- mice developed significantly more spontaneous colon tumors than ApcMin/+ mice and had increased gut permeability before tumor development, associated with reduced expression of E-cadherin. Colon tumors from ApcMin/+Ffar2-/- mice had a higher number of bacteria than tumors from ApcMin/+ mice, as well as higher frequencies of CD39+CD8+ T cells and exhausted or dying T cells. DCs from ApcMin/+Ffar2-/- mice had an altered state of activation, increased death, and higher production of IL27. Administration of an antibody against IL27 reduced the numbers of colon tumors in ApcMin/+ mice with colitis. Frequencies of CD39+CD8+ T cells and IL27+ DCs were increased in colon lamina propria from Ffar2fl/flCD11c-Cre mice with colitis compared with control mice or mice without colitis. ApcMin/+Ffar2fl/flCD11c-Cre mice developed even more tumors than ApcMin/+Ffar2fl/fl mice, and their tumors had even higher numbers of IL27+ DCs. ApcMin/+ mice with colitis given the FFAR2 agonist developed fewer colon tumors, with fewer IL27+ DCs, than mice not given the agonist. DCs incubated with the FFAR2 agonist no longer had gene expression patterns associated with activation or IL27 production.
CONCLUSIONS
Loss of FFAR2 promotes colon tumorigenesis in mice by reducing gut barrier integrity, increasing tumor bacterial load, promoting exhaustion of CD8+ T cells, and overactivating DCs, leading to their death. Antibodies against IL27 and an FFAR2 agonist reduce tumorigenesis in mice and might be developed for the treatment of CRC.
中文翻译：
树突状细胞表达游离脂肪酸受体 2 可阻止其表达白细胞介素 27，并且是维持小鼠粘膜屏障和针对结直肠肿瘤的免疫反应所必需的。
背景与目的肠道微生物及其代谢物影响结直肠癌（CRC）的发展。短链脂肪酸是肠道微生物从膳食纤维产生的代谢产物。我们研究了游离脂肪酸受体 2 (FFAR2)（一种可以影响肠道微生物组组成的短链脂肪酸受体）在 CRC 发病机制中的作用机制。方法 我们对 ApcMin/+ 小鼠、ApcMin/+Ffar2-/- 小鼠、树突状细胞 (DC) 中 Ffar2 条件性破坏的小鼠（Ffar2fl/flCD11c-Cre 小鼠）、ApcMin/+Ffar2fl/flCD11c-Cre 小鼠、和 Ffar2fl/fl 小鼠（对照）；一些小鼠被给予葡聚糖硫酸钠来诱导结肠炎，有或没有 FFAR2 激动剂或白细胞介素 27 (IL27) 抗体。通过组织学、定量聚合酶链反应和 16S 核糖体 RNA 基因测序对结肠和肿瘤组织进行分析；通过RNA测序和流式细胞术分析固有层和肠系膜淋巴结组织。用荧光标记的葡聚糖灌胃后测量肠道通透性。我们从癌症基因组图谱中收集了有关结直肠肿瘤的数据。结果 ApcMin/+Ffar2-/- 小鼠比 ApcMin/+ 小鼠发生明显更多的自发性结肠肿瘤，并且在肿瘤发生前肠道通透性增加，与 E-钙粘蛋白表达减少相关。 ApcMin/+Ffar2-/- 小鼠的结肠肿瘤比 ApcMin/+ 小鼠的结肠肿瘤具有更高的细菌数量，并且 CD39+CD8+ T 细胞和耗尽或死亡的 T 细胞的频率更高。来自 ApcMin/+Ffar2-/- 小鼠的 DC 的激活状态发生改变，死亡增加，IL27 产量增加。 给予 IL27 抗体可减少患有结肠炎的 ApcMin/+ 小鼠的结肠肿瘤数量。与对照小鼠或无结肠炎的小鼠相比，患有结肠炎的 Ffar2fl/flCD11c-Cre 小鼠的结肠固有层中 CD39+CD8+T 细胞和 IL27+DC 的频率增加。 ApcMin/+Ffar2fl/flCD11c-Cre 小鼠比 ApcMin/+Ffar2fl/fl 小鼠产生更多的肿瘤，并且它们的肿瘤具有更多数量的 IL27+ DC。与未给予激动剂的小鼠相比，给予 FFAR2 激动剂的患有结肠炎的 ApcMin/+ 小鼠产生的结肠肿瘤较少，IL27+ DC 也较少。与 FFAR2 激动剂一起孵育的 DC 不再具有与激活或 IL27 产生相关的基因表达模式。结论 FFAR2 的缺失通过降低肠道屏障完整性、增加肿瘤细菌负荷、促进 CD8+ T 细胞耗竭以及过度激活 DC 来促进小鼠结肠肿瘤的发生，从而导致其死亡。 IL27 抗体和 FFAR2 激动剂可减少小鼠肿瘤发生，并可能被开发用于治疗结直肠癌。
更新日期：2020-04-21
中文翻译：
树突状细胞表达游离脂肪酸受体 2 可阻止其表达白细胞介素 27，并且是维持小鼠粘膜屏障和针对结直肠肿瘤的免疫反应所必需的。
背景与目的肠道微生物及其代谢物影响结直肠癌（CRC）的发展。短链脂肪酸是肠道微生物从膳食纤维产生的代谢产物。我们研究了游离脂肪酸受体 2 (FFAR2)（一种可以影响肠道微生物组组成的短链脂肪酸受体）在 CRC 发病机制中的作用机制。方法 我们对 ApcMin/+ 小鼠、ApcMin/+Ffar2-/- 小鼠、树突状细胞 (DC) 中 Ffar2 条件性破坏的小鼠（Ffar2fl/flCD11c-Cre 小鼠）、ApcMin/+Ffar2fl/flCD11c-Cre 小鼠、和 Ffar2fl/fl 小鼠（对照）；一些小鼠被给予葡聚糖硫酸钠来诱导结肠炎，有或没有 FFAR2 激动剂或白细胞介素 27 (IL27) 抗体。通过组织学、定量聚合酶链反应和 16S 核糖体 RNA 基因测序对结肠和肿瘤组织进行分析；通过RNA测序和流式细胞术分析固有层和肠系膜淋巴结组织。用荧光标记的葡聚糖灌胃后测量肠道通透性。我们从癌症基因组图谱中收集了有关结直肠肿瘤的数据。结果 ApcMin/+Ffar2-/- 小鼠比 ApcMin/+ 小鼠发生明显更多的自发性结肠肿瘤，并且在肿瘤发生前肠道通透性增加，与 E-钙粘蛋白表达减少相关。 ApcMin/+Ffar2-/- 小鼠的结肠肿瘤比 ApcMin/+ 小鼠的结肠肿瘤具有更高的细菌数量，并且 CD39+CD8+ T 细胞和耗尽或死亡的 T 细胞的频率更高。来自 ApcMin/+Ffar2-/- 小鼠的 DC 的激活状态发生改变，死亡增加，IL27 产量增加。 给予 IL27 抗体可减少患有结肠炎的 ApcMin/+ 小鼠的结肠肿瘤数量。与对照小鼠或无结肠炎的小鼠相比，患有结肠炎的 Ffar2fl/flCD11c-Cre 小鼠的结肠固有层中 CD39+CD8+T 细胞和 IL27+DC 的频率增加。 ApcMin/+Ffar2fl/flCD11c-Cre 小鼠比 ApcMin/+Ffar2fl/fl 小鼠产生更多的肿瘤，并且它们的肿瘤具有更多数量的 IL27+ DC。与未给予激动剂的小鼠相比，给予 FFAR2 激动剂的患有结肠炎的 ApcMin/+ 小鼠产生的结肠肿瘤较少，IL27+ DC 也较少。与 FFAR2 激动剂一起孵育的 DC 不再具有与激活或 IL27 产生相关的基因表达模式。结论 FFAR2 的缺失通过降低肠道屏障完整性、增加肿瘤细菌负荷、促进 CD8+ T 细胞耗竭以及过度激活 DC 来促进小鼠结肠肿瘤的发生，从而导致其死亡。 IL27 抗体和 FFAR2 激动剂可减少小鼠肿瘤发生，并可能被开发用于治疗结直肠癌。
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