The ATP-hydrolyzing ectoenzyme E-NTPD8 attenuates colitis through modulation of P2X4 receptor-dependent metabolism in myeloid cells.
The ATP-hydrolyzing ectoenzyme E-NTPD8 attenuates colitis through modulation of P2X4 receptor-dependent metabolism in myeloid cells.
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DOI：
10.1073/pnas.2100594118
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发表时间：
2021-09-28
影响因子：
11.1
通讯作者：
Takeda K
中科院分区：
文献类型：
--
作者：
Tani H;Li B;Kusu T;Okumura R;Nishimura J;Okuzaki D;Motooka D;Arakawa S;Mori A;Yoshihara T;Ogino T;Tsai SH;Furuta Y;Muneta M;Nakamura S;Fukusaki E;Yamamoto K;Yagita H;Kayama H;Takeda K
肠道细菌在生长过程中会在腔内产生细胞外 ATP，从而驱动宿主免疫反应。为了避免肠粘膜发生过度免疫反应，对管腔 ATP 进行了微调。然而，人们对如何控制结肠中管腔 ATP 的浓度仍知之甚少。在这里，我们发现 ATP 水解酶 E-NTPD8 在结肠中充当免疫调节剂。 Entpd8 缺陷导致小鼠对 DSS 诱导的结肠炎高度敏感，这是由于结肠中性粒细胞的持续存活所致。细胞外 ATP 通过中性粒细胞中的 P2X4R 诱导代谢改变向糖酵解方向抑制细胞凋亡。这些结果揭示了通过调节骨髓细胞代谢来预防先天性肠道病理的机制，并可能有助于确定 IBD 的治疗靶点。粘膜免疫细胞和肠腔微生物群释放的细胞外三磷酸腺苷 (ATP) 会引发多种免疫反应，通过 P2 嘌呤能受体介导肠道稳态，而 ATP 信号的过度激活会导致粘膜免疫系统破坏，从而导致肠道炎症的发病机制。在小肠中，上皮细胞中的外核苷三磷酸二磷酸水解酶 (E-NTPD)7 对管腔 ATP 的水解对于控制辅助 T 17 (Th17) 细胞的数量至关重要。然而，结肠中微生物群来源的 ATP 受到调节的分子机制仍知之甚少。在这里，我们发现 E-NTPD8 在大肠上皮细胞中高表达，并水解微生物群来源的管腔 ATP。与野生型小鼠相比，Entpd8−/− 小鼠会出现更严重的葡聚糖硫酸钠诱导的结肠炎，可以通过注射抗 Gr-1 抗体消耗中性粒细胞和单核细胞或在造血细胞中引入 P2rx4 缺陷来缓解。 Entpd8−/− 小鼠结肠中管腔 ATP 水平的增加通过 P2x4 受体依赖性 Ca2+ 流入促进中性粒细胞的糖酵解，这与这些细胞的存活时间延长和活性氧产生增加有关。因此，E-NTPD8 通过骨髓细胞中的 P2X4 受体控制糖酵解代谢改变，从而限制肠道炎症。
Intestinal bacteria produce extracellular ATP in the lumen during their growth, which drives host immune responses. To avoid excessive immune reactions in the intestinal mucosa, luminal ATP is finely tuned. However, how the concentration of luminal ATP is controlled in the colon remains poorly understood. Here, we discovered that ATP-hydrolyzing enzyme E-NTPD8 acts as an immunomodulator in the colon. Entpd8 deficiency led to high sensitivity to DSS-induced colitis in mice, which was due to the sustained survival of colonic neutrophils. Extracellular ATP suppressed apoptosis by inducing metabolic alteration toward glycolysis via P2X4R in neutrophils. These results reveal the mechanism preventing innate intestinal pathology through modulation of myeloid cell metabolism and may serve to identify therapeutic targets for IBD. Extracellular adenosine triphosphate (ATP) released by mucosal immune cells and by microbiota in the intestinal lumen elicits diverse immune responses that mediate the intestinal homeostasis via P2 purinergic receptors, while overactivation of ATP signaling leads to mucosal immune system disruption, which leads to pathogenesis of intestinal inflammation. In the small intestine, hydrolysis of luminal ATP by ectonucleoside triphosphate diphosphohydrolase (E-NTPD)7 in epithelial cells is essential for control of the number of T helper 17 (Th17) cells. However, the molecular mechanism by which microbiota-derived ATP in the colon is regulated remains poorly understood. Here, we show that E-NTPD8 is highly expressed in large-intestinal epithelial cells and hydrolyzes microbiota-derived luminal ATP. Compared with wild-type mice, Entpd8−/− mice develop more severe dextran sodium sulfate–induced colitis, which can be ameliorated by either the depletion of neutrophils and monocytes by injecting with anti–Gr-1 antibody or the introduction of P2rx4 deficiency into hematopoietic cells. An increased level of luminal ATP in the colon of Entpd8−/− mice promotes glycolysis in neutrophils through P2x4 receptor–dependent Ca2+ influx, which is linked to prolonged survival and elevated reactive oxygen species production in these cells. Thus, E-NTPD8 limits intestinal inflammation by controlling metabolic alteration toward glycolysis via the P2X4 receptor in myeloid cells.
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影响因子：
3.7
作者：
Furuta Y;Tsai SH;Kinoshita M;Fujimoto K;Okumura R;Umemoto E;Kurashima Y;Kiyono H;Kayama H;Takeda K
通讯作者：
Takeda K
影响因子：
28.3
作者：
Lachmandas, Ekta;Boutens, Lily;Stienstra, Rinke
通讯作者：
Stienstra, Rinke
影响因子：
9.4
作者：
Iwase, Tadayuki;Shinji, Hitomi;Mizunoe, Yoshimitsu
通讯作者：
Mizunoe, Yoshimitsu
DOI：
10.1126/science.aan4665
发表时间：
2018-04-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kornberg MD;Bhargava P;Kim PM;Putluri V;Snowman AM;Putluri N;Calabresi PA;Snyder SH
通讯作者：
Snyder SH
影响因子：
4.4
作者：
Hironaka, Ippei;Iwase, Tadayuki;Mizunoe, Yoshimitsu
通讯作者：
Mizunoe, Yoshimitsu