Targeting Mitochondrial Damage as a Therapeutic for Ileal Crohn's Disease.
Targeting Mitochondrial Damage as a Therapeutic for Ileal Crohn's Disease.
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DOI：
10.3390/cells10061349
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发表时间：
2021-05-29
期刊：
影响因子：
6
通讯作者：
Theiss AL
中科院分区：
文献类型：
--
作者：
Alula KM;Jackson DN;Smith AD;Kim DS;Turner K;Odstrcil E;Kaipparettu BA;Dassopoulos T;Venuprasad K;Feagins LA;Theiss AL
克罗恩病（CD）患者的潘氏细胞缺陷（称为I型表型）与较差的临床结局相关。最近的研究表明潘氏细胞中的线粒体功能障碍是小鼠回肠炎的介导者。我们假设CD Paneth细胞表现出线粒体健康受损，并且回肠靶向治疗可能为回肠CD提供新的策略。对成人CD和非IBD患者的末端回肠粘膜活检进行潘氏细胞表型和线粒体损伤的表征。为了证明髓内靶向治疗剂在CD中的反应，用载体或Mito-Tempo（一种髓内靶向抗氧化剂）处理活检组织，并分析RNA转录组。在活动性CD炎症期间，上皮细胞在潘氏细胞、杯状细胞和肠上皮细胞中表现出明显的线粒体损伤。与炎症无关，I型CD患者的潘氏细胞表现出线粒体损伤。Mito-Tempo将CD患者的白细胞介素（IL）-17/IL-23、脂质代谢和凋亡基因特征的表达标准化至非IBD水平。当按潘氏细胞表型分层时，I型患者对Mito-Tempo的总体组织应答与先天免疫、脂质代谢和G蛋白偶联受体（GPCR）基因特征相关。靶向受损的线粒体作为炎症的潜在贡献者为CD提供了一种新的治疗方法。
Paneth cell defects in Crohn’s disease (CD) patients (called the Type I phenotype) are associated with worse clinical outcomes. Recent studies have implicated mitochondrial dysfunction in Paneth cells as a mediator of ileitis in mice. We hypothesized that CD Paneth cells exhibit impaired mitochondrial health and that mitochondrial-targeted therapeutics may provide a novel strategy for ileal CD. Terminal ileal mucosal biopsies from adult CD and non-IBD patients were characterized for Paneth cell phenotyping and mitochondrial damage. To demonstrate the response of mitochondrial-targeted therapeutics in CD, biopsies were treated with vehicle or Mito-Tempo, a mitochondrial-targeted antioxidant, and RNA transcriptome was analyzed. During active CD inflammation, the epithelium exhibited mitochondrial damage evident in Paneth cells, goblet cells, and enterocytes. Independent of inflammation, Paneth cells in Type I CD patients exhibited mitochondrial damage. Mito-Tempo normalized the expression of interleukin (IL)-17/IL-23, lipid metabolism, and apoptotic gene signatures in CD patients to non-IBD levels. When stratified by Paneth cell phenotype, the global tissue response to Mito-Tempo in Type I patients was associated with innate immune, lipid metabolism, and G protein-coupled receptor (GPCR) gene signatures. Targeting impaired mitochondria as an underlying contributor to inflammation provides a novel treatment approach for CD.
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影响因子：
8
作者：
Ho GT;Aird RE;Liu B;Boyapati RK;Kennedy NA;Dorward DA;Noble CL;Shimizu T;Carter RN;Chew ETS;Morton NM;Rossi AG;Sartor RB;Iredale JP;Satsangi J
通讯作者：
Satsangi J
影响因子：
4.9
作者：
Boyapati, Ray K.;Dorward, David A.;Ho, Gwo-tzer
通讯作者：
Ho, Gwo-tzer
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：
64.5
作者：
Cadwell K;Patel KK;Maloney NS;Liu TC;Ng AC;Storer CE;Head RD;Xavier R;Stappenbeck TS;Virgin HW
通讯作者：
Virgin HW
DOI：
10.1016/s0140-6736(17)30317-3
发表时间：
2017-04-29
期刊：
Lancet (London, England)
影响因子：
--
作者：
Kugathasan S;Denson LA;Walters TD;Kim MO;Marigorta UM;Schirmer M;Mondal K;Liu C;Griffiths A;Noe JD;Crandall WV;Snapper S;Rabizadeh S;Rosh JR;Shapiro JM;Guthery S;Mack DR;Kellermayer R;Kappelman MD;Steiner S;Moulton DE;Keljo D;Cohen S;Oliva-Hemker M;Heyman MB;Otley AR;Baker SS;Evans JS;Kirschner BS;Patel AS;Ziring D;Trapnell BC;Sylvester FA;Stephens MC;Baldassano RN;Markowitz JF;Cho J;Xavier RJ;Huttenhower C;Aronow BJ;Gibson G;Hyams JS;Dubinsky MC
通讯作者：
Dubinsky MC