Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance.
Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance.
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炎症性肠病单核细胞反应的去卷积揭示了一个IL-1细胞因子网络，该网络在遗传和获得性IL-10抵抗中调节IL-23。
DOI：
10.1136/gutjnl-2020-321731
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发表时间：
2021-06
期刊：
影响因子：
24.5
通讯作者：
Uhlig HH
中科院分区：
文献类型：
--
作者：
Aschenbrenner D;Quaranta M;Banerjee S;Ilott N;Jansen J;Steere B;Chen YH;Ho S;Cox K;Arancibia-Cárcamo CV;Coles M;Gaffney E;Travis SP;Denson L;Kugathasan S;Schmitz J;Powrie F;Sansom SN;Uhlig HH
免疫反应失调是IBD的原因。在小鼠和人类中的研究表明，产生白细胞介素（IL）-23的单核吞噬细胞在疾病发病机制中发挥着重要作用。对IL-23调节的机制见解是选择性IL-23靶向治疗作为个性化医疗的一部分的先决条件。我们进行转录组分析来研究IL-23在人单核吞噬细胞和外周血单核细胞中的表达。我们研究了IL-23表达的调节，并使用单细胞RNA测序来获得炎症性单核细胞的转录组特征。使用基因网络相关性分析，我们将该特征解卷积为与患者活检样本中的稳态和炎症相关的组分。我们表征了表达IL-23的健康个体和IBD患者的单核细胞亚群。我们确定IL-1α/IL-1β和IL-10的自感应和旁分泌感应是控制产生IL-23的单核细胞的关键细胞因子。而IL-10受体信号转导中的孟德尔遗传缺陷在脂多糖刺激后诱导IL-23分泌，全菌暴露通过获得性IL-10信号转导抗性诱导对照中的IL-23产生。我们发现了IL-23产生的炎症单核细胞的转录特征，其预测疾病和对抗肿瘤坏死因子（TNF）治疗的抗性，并将其与存在于稳态和疾病中的IL-23相关淋巴细胞分化特征区分开来。我们的工作确定IL-10和IL-1作为单核细胞IL-23产生的关键调节因子。我们在患有严重溃疡性活动性克罗恩病和抗TNF治疗无反应性的患者中区分稳态IL-23产生和炎症相关IL-23产生。总之，我们确定了可能受益于IL-23上游IL-23 p19和/或IL-1α/IL-1β靶向治疗的IBD患者亚组。
Dysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine. We performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA sequencing to derive a transcriptomic signature of hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples. We characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1β and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease. Our work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn’s disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies upstream of IL-23.
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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
DOI：
10.1084/jem.20170057
发表时间：
2018-02-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bujko A;Atlasy N;Landsverk OJB;Richter L;Yaqub S;Horneland R;Øyen O;Aandahl EM;Aabakken L;Stunnenberg HG;Bækkevold ES;Jahnsen FL
通讯作者：
Jahnsen FL
影响因子：
4.5
作者：
Baillie JK;Arner E;Daub C;De Hoon M;Itoh M;Kawaji H;Lassmann T;Carninci P;Forrest AR;Hayashizaki Y;FANTOM Consortium;Faulkner GJ;Wells CA;Rehli M;Pavli P;Summers KM;Hume DA
通讯作者：
Hume DA
影响因子：
56.9
作者：
Duerr, Richard H.;Taylor, Kent D.;Cho, Judy H.
通讯作者：
Cho, Judy H.
影响因子：
64.5
作者：
Dixit, Atray;Pamas, Oren;Li, Biyu;Chen, Jenny;Fulco, Charles P.;Jerby-Amon, Livnat;Marjanovic, Nemanja D.;Dionne, Danielle;Burks, Tyler;Raychowdhury, Raktima;Adamson, Britt;Norman, Thomas M.;Lander, Eric S.;Weissman, Jonathan S.;Friedman, Nir;Regev, Aviv
通讯作者：
Regev, Aviv