A. Muciniphila Suppresses Colorectal Tumorigenesis by Inducing TLR2/NLRP3-Mediated M1-Like TAMs
A. Muciniphila Suppresses Colorectal Tumorigenesis by Inducing TLR2/NLRP3-Mediated M1-Like TAMs
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DOI：
10.1158/2326-6066.cir-20-1019
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发表时间：
2021-10-01
影响因子：
10.1
通讯作者：
Wang, Liangjing
中科院分区：
文献类型：
--
作者：
Fan, Lina;Xu, Chaochao;Wang, Liangjing
肠道微生物群和宿主免疫系统之间的相互作用正在成为结直肠癌发病机制中的一个因素。在这里，我们着手确定嗜粘蛋白阿克曼氏菌（A. muciniphila）对结直肠癌发病机制的影响。A.在来自两个独立的临床队列和GMrepo数据集的结直肠癌患者中，嗜粘蛋白体丰度显著降低。以A.在Apc（Min/+）小鼠中，嗜粘蛋白菌抑制结肠肿瘤发生，在裸鼠中抑制植入的HCT 116或CT 26肿瘤的生长。机械地，A。在体内和体外，muciniphila以NLRP 3依赖性方式促进M1样巨噬细胞的富集。因此，巨噬细胞中的NLRP 3缺陷减弱了A.嗜粘蛋白菌。此外，我们发现TLR 2对NF-κ B B/NLRP 3通路和A. muciniphila诱导M1样巨噬细胞反应。M1样巨噬细胞、NLRP 3/TLR 2和A.结直肠癌患者中的嗜粘蛋白，这证实了这些发现。综上所述，A.嗜粘蛋白诱导的M1样巨噬细胞在结肠直肠癌肿瘤微环境中提供了治疗靶点。
The interplay between gut microbiota and the host immune system is emerging as a factor in the pathogenesis of colorectal cancer. Here, we set out to identify the effect of Akkermansia muciniphila (A. muciniphila) on colorectal cancer pathogenesis. A. muciniphila abundance was significantly reduced in patients with colorectal cancer from two independent clinical cohorts and the GMrepo dataset. Supplementation with A. muciniphila suppressed colonic tumorigenesis in Apc(Min/+) mice and the growth of implanted HCT116 or CT26 tumors in nude mice. Mechanistically, A. muciniphila facilitated enrichment of M1-like macrophages in an NLRP3-dependent manner in vivo and in vitro. As a consequence, NLRP3 deficiency in macrophages attenuated the tumor-suppressive effect of A. muciniphila. In addition, we revealed that TLR2 was essential for the activation of the NF-kappa B/NLRP3 pathway and A. muciniphila induced M1-like macrophage response. We observed positive correlations between M1-like macrophages, NLRP3/TLR2 and A. muciniphila in patients with colorectal cancer, which corroborated these findings. In summary, A. muciniphila induced M1-like macrophages provide a therapeutic target in the colorectal cancer tumor microenvironment.