Inflamed Ulcerative Colitis Regions Associated With MRGPRX2-Mediated Mast Cell Degranulation and Cell Activation Modules, Defining a New Therapeutic Target.
Inflamed Ulcerative Colitis Regions Associated With MRGPRX2-Mediated Mast Cell Degranulation and Cell Activation Modules, Defining a New Therapeutic Target.
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DOI：
10.1053/j.gastro.2020.12.076
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发表时间：
2021-04
期刊：
影响因子：
29.4
通讯作者：
Cho JH
中科院分区：
文献类型：
--
作者：
Chen E;Chuang LS;Giri M;Villaverde N;Hsu NY;Sabic K;Joshowitz S;Gettler K;Nayar S;Chai Z;Alter IL;Chasteau CC;Korie UM;Dzedzik S;Thin TH;Jain A;Moscati A;Bongers G;Duerr RH;Silverberg MS;Brant SR;Rioux JD;Peter I;Schumm LP;Haritunians T;McGovern DP;Itan Y;Cho JH
最近的文献表明肥大细胞在小鼠结肠炎症模型中起着关键作用，但它们在人类溃疡性结肠炎（UC）中的作用还没有得到很好的证实。一个主要的进展是鉴定了mrgprb 2（人直系同源物，MRGPX 2）介导IgE非依赖性肥大细胞活化。我们试图确定肥大细胞活化和MRGPRX 2在人类UC中的机制。从UC患者收集结肠组织用于批量RNAseq，并分离固有层细胞用于MRGPRX 2活化研究和单细胞RNA测序（scRNAseq）。在德系犹太人UC病例对照队列中进行所有蛋白质改变GPCR SNP的遗传关联。将MRGPRX 2的变体转染到CHO和HMC-1.1细胞中，以检测对β-抑制蛋白募集、IP-1蓄积和磷酸化ERK的基因型依赖性效应。肥大细胞特异性介质和ADM（肾上腺髓质素，PAMP-12的蛋白水解前体，一种MRGPRX 2激动剂）在炎症UC中比未炎症UC上调。MRGPRX 2刺激诱导羧肽酶从发炎UC分泌。在所有改变蛋白质的GPCR等位基因中，MRGPRX 2的独特变体Asn 62 Ser最相关，生物信息学预测可改变arrestin募集。我们验证了UC保护性丝氨酸等位基因增强β-抑制蛋白募集，减少IP-1，并增加MRGPRX 2激动剂的磷酸化ERK。scRNASeq定义ADM由活化的成纤维细胞和上皮细胞表达，IFNG是肥大细胞基因表达的关键上游调节因子。炎症UC区域通过MRGPRX 2介导的肥大细胞活化来区分，观察到UC保护性遗传变异体的活化降低。这些结果定义了UC激活的细胞模块和新的治疗靶点。发炎的溃疡性结肠炎区域表现出MRGPRX 2介导的活化肥大细胞的脱粒，与未发炎的结肠相比暗示正反馈炎症循环。MRGPRX 2中功能丧失的保护性丝氨酸等位基因的鉴定和功能验证为溃疡性结肠炎定义了一个新的治疗靶点。发炎的溃疡性结肠炎区域表现为G蛋白偶联受体（GPCR）介导的肥大细胞脱粒。功能丧失的保护性GPCR等位基因的鉴定为溃疡性结肠炎定义了新的治疗靶点。
Recent literature has implicated a key role for mast cells in murine models of colonic inflammation, but their role in human ulcerative colitis (UC) is not well-established. A major advance has been the identification of mrgprb2 (human orthologue, MRGPX2) as mediating IgE-independent mast cell activation. We sought to define mechanisms of mast cell activation and MRGPRX2 in human UC. Colon tissues were collected from UC patients for bulk RNAseq and lamina propria cells were isolated for MRGPRX2 activation studies and single-cell RNA sequencing (scRNAseq). Genetic association of all protein altering GPCR SNPs was performed in an Ashkenazi Jewish UC case-control cohort. Variants of MRGPRX2 were transfected into CHO and HMC-1.1 cells to detect genotype-dependent effects on β-arrestin recruitment, IP-1 accumulation, and phosphoERK. Mast cell-specific mediators and ADM (adrenomedullin, proteolytic precursor of PAMP-12, an MRGPRX2 agonist) are upregulated in inflamed compared to uninflamed UC. MRGPRX2 stimulation induces carboxypeptidase secretion from inflamed UC. Of all protein-altering GPCR alleles, a unique variant of MRGPRX2, Asn62Ser, was most associated, bioinformatically predicted to alter arrestin recruitment. We validated that the UC protective serine allele enhances beta-arrestin recruitment, decreases IP-1, and increases phosphoERK with MRGPRX2 agonists. scRNASeq defines that ADM is expressed by activated fibroblasts and epithelial cells, and that IFNG is a key, upstream regulator of mast cell gene expression. Inflamed UC regions are distinguished by MRGPRX2-mediated activation of mast cells, with decreased activation observed with a UC-protective genetic variant. These results define cell modules of UC activation and a new therapeutic target. Inflamed ulcerative colitis regions demonstrate MRGPRX2-mediated degranulation of activated mast cells, implicating a positive feedback inflammatory loop compared to uninflamed colon. The identification and functional validation of a loss-of-function, protective serine allele in MRGPRX2 defines a new therapeutic target for ulcerative colitis. Inflamed ulcerative colitis regions demonstrate G-protein coupled receptor (GPCR)-mediated degranulation of mast cells. The identification of a loss-of-function, protective GPCR allele defines a new therapeutic target for ulcerative colitis.
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影响因子：
8
作者：
Schwerd T;Bryant RV;Pandey S;Capitani M;Meran L;Cazier JB;Jung J;Mondal K;Parkes M;Mathew CG;Fiedler K;McCarthy DJ;WGS500 Consortium;Oxford IBD cohort study investigators;COLORS in IBD group investigators;UK IBD Genetics Consortium;Sullivan PB;Rodrigues A;Travis SPL;Moore C;Sambrook J;Ouwehand WH;Roberts DJ;Danesh J;INTERVAL Study;Russell RK;Wilson DC;Kelsen JR;Cornall R;Denson LA;Kugathasan S;Knaus UG;Serra EG;Anderson CA;Duerr RH;McGovern DP;Cho J;Powrie F;Li VS;Muise AM;Uhlig HH
通讯作者：
Uhlig HH
克罗恩病和溃疡性结肠炎表型的遗传决定因素：遗传关联研究。
DOI：
10.1016/s0140-6736(15)00465-1
发表时间：
2016-01-09
期刊：
Lancet (London, England)
影响因子：
--
作者：
Cleynen I;Boucher G;Jostins L;Schumm LP;Zeissig S;Ahmad T;Andersen V;Andrews JM;Annese V;Brand S;Brant SR;Cho JH;Daly MJ;Dubinsky M;Duerr RH;Ferguson LR;Franke A;Gearry RB;Goyette P;Hakonarson H;Halfvarson J;Hov JR;Huang H;Kennedy NA;Kupcinskas L;Lawrance IC;Lee JC;Satsangi J;Schreiber S;Théâtre E;van der Meulen-de Jong AE;Weersma RK;Wilson DC;International Inflammatory Bowel Disease Genetics Consortium;Parkes M;Vermeire S;Rioux JD;Mansfield J;Silverberg MS;Radford-Smith G;McGovern DP;Barrett JC;Lees CW
通讯作者：
Lees CW
影响因子：
64.5
作者：
Hauser AS;Chavali S;Masuho I;Jahn LJ;Martemyanov KA;Gloriam DE;Babu MM
通讯作者：
Babu MM
DOI：
10.1016/j.bbrc.2005.03.088
发表时间：
2005-05-20
影响因子：
3.1
作者：
Kamohara, M;Matsuo, A;Katou, M
通讯作者：
Katou, M
影响因子：
64.5
作者：
Foster, Simon R.;Hauser, Alexander S.;Gloriam, David E.
通讯作者：
Gloriam, David E.