Aryl hydrocarbon receptor nuclear translocator limits the recruitment and function of regulatory neutrophils against colorectal cancer by regulating the gut microbiota.
Aryl hydrocarbon receptor nuclear translocator limits the recruitment and function of regulatory neutrophils against colorectal cancer by regulating the gut microbiota.
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DOI：
10.1186/s13046-023-02627-y
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发表时间：
2023-03-01
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影响因子：
--
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虽然中性粒细胞在肿瘤中的作用和机制已被广泛研究，但芳烃受体核转运子（ARNT）对中性粒细胞的确切作用尚不清楚。在这项研究中，我们研究了ARNT在结肠炎相关结直肠癌中CD11b+Gr1+中性粒细胞功能中的作用。本研究使用野生型（WT）、ARNT骨髓特异性缺陷小鼠和结肠炎相关结直肠癌小鼠模型。用流式细胞术和共聚焦显微镜观察CD11b+Gr1+细胞的表达水平和功能。我们发现，当结直肠肿瘤发生时，当细胞从骨髓进入外周时，ARNT缺乏驱动中性粒细胞募集、中性粒细胞胞外陷阱（NET）的发育、炎症细胞因子的分泌和抑制活性。中性粒细胞中ARNT缺乏表现出与芳烃受体（AHR）缺乏相似的影响。在结直肠癌中，CXCR2是NET发育、细胞因子产生和中性粒细胞募集所必需的，但不是Arnt - / -诱导的抑制活性所必需的。肠道微生物群对Arnt - / -中性粒细胞功能改变促进结直肠癌生长至关重要。小鼠共住或抗生素治疗可显著恢复Arnt - / -中性粒细胞对结直肠癌的影响。Arnt - / -小鼠粪便灌胃可观察其对结直肠癌的影响。我们的研究结果确定了转录因子ARNT在调节中性粒细胞募集和功能以及肠道微生物群中的新作用，这对未来肠道微生物群和免疫治疗方法在结直肠癌中的结合具有重要意义。在线版本包含补充材料，可在10.1186/s13046-023-02627-y获得。
Although the role and mechanism of neutrophils in tumors have been widely studied, the precise effects of aryl hydrocarbon receptor nuclear translocator (ARNT) on neutrophils remain unclear. In this study, we investigated the roles of ARNT in the function of CD11b+Gr1+ neutrophils in colitis-associated colorectal cancer. Wild-type (WT), ARNT myeloid-specific deficient mice and a colitis-associated colorectal cancer mouse model were used in this study. The level and functions of CD11b+Gr1+ cells were evaluated by flow cytometry and confocal microscopy. We found that ARNT deficiency drives neutrophils recruitment, neutrophil extracellular trap (NET) development, inflammatory cytokine secretion and suppressive activities when cells enter the periphery from bone marrow upon colorectal tumorigenesis. ARNT deficiency displays similar effects to aryl hydrocarbon receptor (AHR) deficiency in neutrophils. CXCR2 is required for NET development, cytokine production and recruitment of neutrophils but not the suppressive activities induced by Arnt−/− in colorectal cancer. The gut microbiota is essential for functional alterations in Arnt−/− neutrophils to promote colorectal cancer growth. The colorectal cancer effects of Arnt−/− neutrophils were significantly restored by mouse cohousing or antibiotic treatment. Intragastric administration of the feces of Arnt−/− mice phenocopied their colorectal cancer effects. Our results defined a new role for the transcription factor ARNT in regulating neutrophils recruitment and function and the gut microbiota with implications for the future combination of gut microbiota and immunotherapy approaches in colorectal cancer. The online version contains supplementary material available at 10.1186/s13046-023-02627-y.
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影响因子：
22.7
作者：
Li T;Li X;Zamani A;Wang W;Lee CN;Li M;Luo G;Eiler E;Sun H;Ghosh S;Jin J;Murali R;Ruan Q;Shi W;Chen YH
通讯作者：
Chen YH
影响因子：
16.6
作者：
Li C;Bi Y;Li Y;Yang H;Yu Q;Wang J;Wang Y;Su H;Jia A;Hu Y;Han L;Zhang J;Li S;Tao W;Liu G
通讯作者：
Liu G
影响因子：
11.2
作者：
Liu, Guangwei;Bi, Yujing;Chu, Yiwei
通讯作者：
Chu, Yiwei
影响因子：
3.6
作者：
Choi, Hyunsung;Chun, Yang-Sook;Park, Jong-Wan
通讯作者：
Park, Jong-Wan
影响因子：
254.7
作者：
Siegel, Rebecca L.;Miller, Kimberly D.;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin