Cholesterol sulfate limits neutrophil recruitment and gut inflammation during mucosal injury.
Cholesterol sulfate limits neutrophil recruitment and gut inflammation during mucosal injury.
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DOI：
10.3389/fimmu.2023.1131146
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
在粘膜损伤过程中，肠道免疫细胞在清除入侵细菌方面起着至关重要的作用。然而，由于免疫细胞的过度积累会促进炎症并延迟组织修复，因此必须确定限制免疫细胞浸润到粘膜-管腔界面的机制。硫酸胆固醇（CS）是磺基转移酶SULT 2B 1的脂质产物，通过抑制DOCK 2介导的Rac活化来抑制免疫反应。在这项研究中，我们的目的是阐明CS在肠道中的生理作用。我们发现，在小肠和结肠中，CS主要产生于靠近管腔的上皮细胞中。虽然葡聚糖硫酸钠（DSS）诱导的结肠炎在Sult 2b 1缺陷小鼠中加重，中性粒细胞的患病率增加，但在Sult 2b 1缺陷小鼠中消除中性粒细胞或肠道细菌可减轻疾病的发展。当在Sult 2b 1缺陷小鼠中Dock 2基因缺失时，获得了类似的结果。此外，我们还表明，吲哚美辛诱导的小肠溃疡形成加剧Sult 2b 1缺陷小鼠和CS管理得到改善。因此，我们的研究结果揭示了CS作用于炎性中性粒细胞，并通过抑制Rac激活剂DOCK 2来防止过度的肠道炎症。CS给药可能是炎症性肠病和非甾体抗炎药诱导的溃疡的一种新的治疗策略。
During mucosal injury, intestinal immune cells play a crucial role in eliminating invading bacteria. However, as the excessive accumulation of immune cells promotes inflammation and delays tissue repair, it is essential to identify the mechanism that limits the infiltration of immune cells to the mucosal-luminal interface. Cholesterol sulfate (CS) is the lipid product of the sulfotransferase SULT2B1 and suppresses immune reactions by inhibiting DOCK2-mediated Rac activation. In this study, we aimed to elucidate the physiological role of CS in the intestinal tract. We found that, in the small intestine and colon, CS is predominantly produced in the epithelial cells close to the lumen. While dextran sodium sulfate (DSS)-induced colitis was exacerbated in Sult2b1-deficient mice with increased prevalence of neutrophils, the elimination of either neutrophils or intestinal bacteria in Sult2b1-deficient mice attenuated disease development. Similar results were obtained when the Dock2 was genetically deleted in Sult2b1-deficient mice. In addition, we also show that indomethacin-induced ulcer formation in the small intestine was exacerbated in Sult2b1-deficient mice and was ameliorated by CS administration. Thus, our results uncover that CS acts on inflammatory neutrophils, and prevents excessive gut inflammation by inhibiting the Rac activator DOCK2. The administration of CS may be a novel therapeutic strategy for inflammatory bowel disease and non-steroidal anti-inflammatory drug-induced ulcers.
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早发作感染患者的遗传DOCK2缺乏。
DOI：
10.1056/nejmoa1413462
发表时间：
2015-06-18
期刊：
The New England journal of medicine
影响因子：
--
作者：
Dobbs K;Domínguez Conde C;Zhang SY;Parolini S;Audry M;Chou J;Haapaniemi E;Keles S;Bilic I;Okada S;Massaad MJ;Rounioja S;Alwahadneh AM;Serwas NK;Capuder K;Çiftçi E;Felgentreff K;Ohsumi TK;Pedergnana V;Boisson B;Haskoloğlu Ş;Ensari A;Schuster M;Moretta A;Itan Y;Patrizi O;Rozenberg F;Lebon P;Saarela J;Knip M;Petrovski S;Goldstein DB;Parrott RE;Savas B;Schambach A;Tabellini G;Bock C;Chatila TA;Comeau AM;Geha RS;Abel L;Buckley RH;İkincioğulları A;Al-Herz W;Helminen M;Doğu F;Casanova JL;Boztuğ K;Notarangelo LD
通讯作者：
Notarangelo LD
影响因子：
10.5
作者：
Laurin M;Côté JF
通讯作者：
Côté JF
影响因子：
16.6
作者：
Haberman, Yael;Karns, Rebekah;Denson, Lee A.
通讯作者：
Denson, Lee A.
影响因子：
16.6
作者：
Kurashima Y;Kigoshi T;Murasaki S;Arai F;Shimada K;Seki N;Kim YG;Hase K;Ohno H;Kawano K;Ashida H;Suzuki T;Morimoto M;Saito Y;Sasou A;Goda Y;Yuki Y;Inagaki Y;Iijima H;Suda W;Hattori M;Kiyono H
通讯作者：
Kiyono H
影响因子：
7.8
作者：
Kunisaki, Yuya;Nishikimi, Akihiko;Tanaka, Yoshihiko;Takii, Ryosuke;Noda, Mayuko;Inayoshi, Ayumi;Watanabe, Ken-ichi;Sanematsu, Fumiyuki;Sasazuki, Takehiko;Sasaki, Takehiko;Fukui, Yoshinori
通讯作者：
Fukui, Yoshinori