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Inducible pluripotent stem cells to study human mast cell trajectories 研究人类肥大细胞轨迹的可诱导多能干细胞。
IF 7.9 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.07.003
<div><div>Mast cells (MCs) are derived from CD34<sup>+</sup> hematopoietic progenitors, consist of different subtypes, and are involved in several inflammatory conditions. However, our understanding of human MC developmental trajectories and subtypes has been limited by a scarcity of suitable cellular model systems. Herein, we developed an <em>in vitro</em> model of human MC differentiation from induced pluripotent stem cells (iPSC) to study human MC differentiation trajectories. Flow cytometry characterization of hemopoietic cells derived from the myeloid cells-forming complex (MCFC) revealed an initial increase in Lin<sup>-</sup> CD34<sup>+</sup> hematopoietic progenitors within Weeks 1–3, followed by an increase in CD34<sup>-</sup> CD45RA<sup>-</sup> SSC<sup>l</sup><sup>ow</sup> and SSC<sup>high</sup> hematopoietic cells. The Lin<sup>-</sup> CD34<sup>+</sup> hematopoietic progenitors consisted of SSC<sup>low</sup> CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>+</sup> FcεRI<sup>+</sup> populations that were β7-integrin<sup>high</sup> CD203c<sup>+</sup> and β7-integrin<sup>high</sup> CD203c<sup>-</sup> cells consistent with CMP<sup>Fc</sup><sup>ε</sup><sup>RI+</sup> cells. Flow cytometry and cytologic analyses of the CD34<sup>-</sup> Lin<sup>-</sup> (SSC<sup>low</sup>) population revealed hypogranular cell populations, predominantly characterized by CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>+</sup> FcεRI<sup>-</sup> β7-integrin<sup>low</sup> and CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>-</sup> FcεRI<sup>+</sup> β7-integrin<sup>Mid</sup> cells. Analyses of hypergranular SSC<sup>high</sup> cells identified Lin<sup>-</sup> CD34<sup>-</sup> CD45RA<sup>-</sup> c-Kit<sup>+</sup> FcεRI<sup>-</sup> and Lin<sup>-</sup> CD34<sup>-</sup> CD45RA<sup>-</sup> c-Kit<sup>+</sup> FcεRI<sup>+</sup> cells. scRNA-seq analysis of the cells harvested at week 4 of the MCFC culture revealed the presence of monocyte and granulocyte progenitors (n = 547 cells, 26.7 %), Erythrocyte / unknown (n = 85, 4.1 %), neutrophils / myelocytes (n = 211 cells, 10.2 %), mast cell progenitor 1 (n = 599, 29.1 %), mast cell progenitor 2 (n = 152, 7.4 %), committed mast cell precursor (n = 113, 5.5 %), and MCs (n = 353, 17.1 %). In silico analyses of the MC precursor and mature MC populations revealed transcriptionally distinct MC precursor subtype and mature MC states (CMA1<sup>+</sup> and CMA1<sup>-</sup> subtypes). Culturing MC precursor populations in MC maturation media (mast cell media II) led to homogenous mature MC populations as evidenced by high expression of high-affinity IgE receptor, metachromatic granules, presence of MC granule proteins (Tryptase and Chymase) and activation following substance P stimulation and FcεRI crosslinking. This human iPSC-based approach generates MC precursors and phenotypically mature and functional MC populations. This system will be a useful model to generate human MC populations and broaden our understanding of MC biology and transcr
肥大细胞(MC)来源于 CD34+ 造血祖细胞,由不同的亚型组成,参与多种炎症的治疗。然而,由于缺乏合适的细胞模型系统,我们对人类 MC 发育轨迹和亚型的了解受到了限制。在此,我们利用诱导多能干细胞(iPSC)建立了人类 MC 分化的体外模型,以研究人类 MC 的分化轨迹。流式细胞术鉴定了来自髓系细胞形成复合体(MCFC)的造血细胞,发现在第1-3周,Lin- CD34+造血祖细胞开始增加,随后CD34- CD45RA- SSCLow和SSChigh造血细胞增加。Lin- CD34+ 造血祖细胞由 SSClow CD45RA- CD123± c-Kit+ FcERI+ 群体组成,该群体为 β7-integrinhigh CD203c+ 和 β7-integrinhigh CD203c- 细胞,与 CMPFceRI+ 细胞一致。对CD34- Lin-(SSClow)群体的流式细胞术和细胞学分析显示了低颗粒细胞群,主要特征是CD45RA- CD123± c-Kit+ FcERI- β7-integrin-low和CD45RA- CD123± c-Kit- FcERI+ β7-integrin-Mid细胞。对超粒 SSChigh 细胞的分析发现了 Lin- CD34- CD45RA- c-Kit+ FceRI- 和 Lin- CD34- CD45RA- c-Kit+ FceRI+ 细胞。对 MCFC 培养第 4 周收获的细胞进行的 scRNA seq 分析显示存在单核细胞和粒细胞祖细胞(n = 547 个细胞,26.7 %)、红细胞/未知细胞(n = 85,4.1 %)、中性粒细胞/骨髓细胞(n = 211,10.2 %)、肥大细胞祖细胞 1(n = 599,29.1 %)、肥大细胞祖细胞 2(n = 152,7.4 %)、肥大细胞前体(n = 113,5.5 %)和肥大细胞(n = 353,17.1 %)。对肥大细胞前体和成熟肥大细胞群进行的硅学分析表明,肥大细胞前体亚型和成熟肥大细胞状态(CMA1+ 和 CMA1-亚型)在转录上截然不同。在 MC 成熟培养基(肥大细胞培养基 II)中培养 MC 前体群体可产生同质的成熟 MC 群体,表现为高亲和力 IgE 受体的高表达、变色颗粒、MC 颗粒蛋白(胰蛋白酶和糜蛋白酶)的存在以及物质 P 刺激和 FceRI 交联后的活化。这种基于人类 iPSC 的方法可产生 MC 前体和表型成熟的功能性 MC 群体。该系统将成为产生人类 MC 群体的有用模型,并拓宽我们对 MC 生物学和 MC 分化轨迹转录调控的理解。
{"title":"Inducible pluripotent stem cells to study human mast cell trajectories","authors":"","doi":"10.1016/j.mucimm.2024.07.003","DOIUrl":"10.1016/j.mucimm.2024.07.003","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Mast cells (MCs) are derived from CD34&lt;sup&gt;+&lt;/sup&gt; hematopoietic progenitors, consist of different subtypes, and are involved in several inflammatory conditions. However, our understanding of human MC developmental trajectories and subtypes has been limited by a scarcity of suitable cellular model systems. Herein, we developed an &lt;em&gt;in vitro&lt;/em&gt; model of human MC differentiation from induced pluripotent stem cells (iPSC) to study human MC differentiation trajectories. Flow cytometry characterization of hemopoietic cells derived from the myeloid cells-forming complex (MCFC) revealed an initial increase in Lin&lt;sup&gt;-&lt;/sup&gt; CD34&lt;sup&gt;+&lt;/sup&gt; hematopoietic progenitors within Weeks 1–3, followed by an increase in CD34&lt;sup&gt;-&lt;/sup&gt; CD45RA&lt;sup&gt;-&lt;/sup&gt; SSC&lt;sup&gt;l&lt;/sup&gt;&lt;sup&gt;ow&lt;/sup&gt; and SSC&lt;sup&gt;high&lt;/sup&gt; hematopoietic cells. The Lin&lt;sup&gt;-&lt;/sup&gt; CD34&lt;sup&gt;+&lt;/sup&gt; hematopoietic progenitors consisted of SSC&lt;sup&gt;low&lt;/sup&gt; CD45RA&lt;sup&gt;-&lt;/sup&gt; CD123&lt;sup&gt;±&lt;/sup&gt; c-Kit&lt;sup&gt;+&lt;/sup&gt; FcεRI&lt;sup&gt;+&lt;/sup&gt; populations that were β7-integrin&lt;sup&gt;high&lt;/sup&gt; CD203c&lt;sup&gt;+&lt;/sup&gt; and β7-integrin&lt;sup&gt;high&lt;/sup&gt; CD203c&lt;sup&gt;-&lt;/sup&gt; cells consistent with CMP&lt;sup&gt;Fc&lt;/sup&gt;&lt;sup&gt;ε&lt;/sup&gt;&lt;sup&gt;RI+&lt;/sup&gt; cells. Flow cytometry and cytologic analyses of the CD34&lt;sup&gt;-&lt;/sup&gt; Lin&lt;sup&gt;-&lt;/sup&gt; (SSC&lt;sup&gt;low&lt;/sup&gt;) population revealed hypogranular cell populations, predominantly characterized by CD45RA&lt;sup&gt;-&lt;/sup&gt; CD123&lt;sup&gt;±&lt;/sup&gt; c-Kit&lt;sup&gt;+&lt;/sup&gt; FcεRI&lt;sup&gt;-&lt;/sup&gt; β7-integrin&lt;sup&gt;low&lt;/sup&gt; and CD45RA&lt;sup&gt;-&lt;/sup&gt; CD123&lt;sup&gt;±&lt;/sup&gt; c-Kit&lt;sup&gt;-&lt;/sup&gt; FcεRI&lt;sup&gt;+&lt;/sup&gt; β7-integrin&lt;sup&gt;Mid&lt;/sup&gt; cells. Analyses of hypergranular SSC&lt;sup&gt;high&lt;/sup&gt; cells identified Lin&lt;sup&gt;-&lt;/sup&gt; CD34&lt;sup&gt;-&lt;/sup&gt; CD45RA&lt;sup&gt;-&lt;/sup&gt; c-Kit&lt;sup&gt;+&lt;/sup&gt; FcεRI&lt;sup&gt;-&lt;/sup&gt; and Lin&lt;sup&gt;-&lt;/sup&gt; CD34&lt;sup&gt;-&lt;/sup&gt; CD45RA&lt;sup&gt;-&lt;/sup&gt; c-Kit&lt;sup&gt;+&lt;/sup&gt; FcεRI&lt;sup&gt;+&lt;/sup&gt; cells. scRNA-seq analysis of the cells harvested at week 4 of the MCFC culture revealed the presence of monocyte and granulocyte progenitors (n = 547 cells, 26.7 %), Erythrocyte / unknown (n = 85, 4.1 %), neutrophils / myelocytes (n = 211 cells, 10.2 %), mast cell progenitor 1 (n = 599, 29.1 %), mast cell progenitor 2 (n = 152, 7.4 %), committed mast cell precursor (n = 113, 5.5 %), and MCs (n = 353, 17.1 %). In silico analyses of the MC precursor and mature MC populations revealed transcriptionally distinct MC precursor subtype and mature MC states (CMA1&lt;sup&gt;+&lt;/sup&gt; and CMA1&lt;sup&gt;-&lt;/sup&gt; subtypes). Culturing MC precursor populations in MC maturation media (mast cell media II) led to homogenous mature MC populations as evidenced by high expression of high-affinity IgE receptor, metachromatic granules, presence of MC granule proteins (Tryptase and Chymase) and activation following substance P stimulation and FcεRI crosslinking. This human iPSC-based approach generates MC precursors and phenotypically mature and functional MC populations. This system will be a useful model to generate human MC populations and broaden our understanding of MC biology and transcr","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CSF1-dependent macrophage support matrisome and epithelial stress-induced keratin remodeling in Eosinophilic esophagitis. 嗜酸性粒细胞食管炎中依赖 CSF1 的巨噬细胞支持 matrisome 和上皮应激诱导的角蛋白重塑
IF 7.9 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-27 DOI: 10.1016/j.mucimm.2024.09.006
Taylor M Benson, Gary E Markey, Juliet A Hammer, Luke Simerly, Monika Dzieciatkowska, Kimberly R Jordan, Kelley E Capocelli, Kathleen M Scullion, Louise Crowe, Sinéad Ryan, Jennifer O Black, Taylor Crue, Rachel Andrews, Cassandra Burger, Eóin N McNamee, Glenn T Furuta, Calies Menard-Katcher, Joanne C Masterson

Atopic diseases such as Eosinophilic Esophagitis (EoE) often progress into fibrosis (FS-EoE), compromising organ function with limited targeted treatment options. Mechanistic understanding of FS-EoE progression is confounded by the lack of preclinical models and the heavy focus of research on eosinophils themselves. We found that macrophage accumulation precedes esophageal fibrosis in FS-EoE patients. We developed a FS-EoE model via chronic administration of oxazalone allergen, in a transgenic mouse over-expressing esophageal epithelial hIL-5 (L2-IL5OXA). These mice display striking histopathologic features congruent with that found in FS-EoE patients. Unbiased proteomic analysis, using a unique extracellular-matrix (ECM) focused technique, identified an inflammation-reactive provisional basal lamina membrane signature and this was validated in two independent EoE patient RNA-sequencing/proteomic cohorts, supporting model significance. A wound healing signature was also observed involving hemostasis-associated molecules previously unnoted in EoE. We further identified the ECM glycoprotein, Tenascin-C (TNC), and the stress-responsive keratin-16 (KRT16) as IL-4 and IL-13 responsive mediators, acting as biomarkers of FS-EoE. To mechanistically address how the immune infiltrate shapes FS-EoE progression, we phenotyped the major immune cell subsets that coalesce with fibrosis in both the L2-IL5OXA mice and in FS-EoE patients. We found that macrophage are required for matrisome and cytoskeletal remodeling. Importantly, we show that macrophage accumulation precedes esophageal fibrosis and provide a novel therapeutic target in FS-EoE as their depletion with anti-CSF1 attenuated reactive matrisome and cytoskeletal changes. Thus, macrophage-based treatments and the exploration of TNC and KRT16 as biomarkers may provide novel therapeutic options for patients with fibrostenosis.

嗜酸性粒细胞食管炎(EoE)等变应性疾病通常会发展为纤维化(FS-EoE),损害器官功能,但针对性治疗方案却很有限。由于缺乏临床前模型,而且研究重点主要集中在嗜酸性粒细胞本身,因此对FS-EoE进展机制的理解受到了困惑。我们发现,在 FS-EoE 患者中,巨噬细胞聚集先于食管纤维化。我们通过在过度表达食管上皮 hIL-5 的转基因小鼠(L2-IL5OXA)中长期给予噁唑酮过敏原,建立了 FS-EoE 模型。这些小鼠显示出与 FS-EoE 患者一致的惊人组织病理学特征。利用独特的细胞外基质(ECM)聚焦技术进行的无偏蛋白质组分析确定了炎症反应性临时基底层膜特征,并在两个独立的EoE患者RNA测序/蛋白质组队列中得到了验证,证明了模型的重要性。我们还观察到了一种伤口愈合特征,其中涉及到以前在肠炎中未注意到的止血相关分子。我们进一步确定了 ECM 糖蛋白 Tenascin-C (TNC) 和应激反应性角蛋白-16 (KRT16) 作为 IL-4 和 IL-13 反应介质,可作为 FS-EoE 的生物标志物。为了从机理上探讨免疫浸润如何影响 FS-EoE 的进展,我们对在 L2-IL5OXA 小鼠和 FS-EoE 患者中与纤维化聚集在一起的主要免疫细胞亚群进行了表型分析。我们发现,巨噬细胞是基质组和细胞骨架重塑所必需的。重要的是,我们发现巨噬细胞的聚集先于食管纤维化,并为 FS-EoE 提供了一个新的治疗靶点,因为用抗-CSF1 清除巨噬细胞可减轻反应性基质组和细胞骨架的变化。因此,以巨噬细胞为基础的治疗方法以及将 TNC 和 KRT16 作为生物标记物的探索可能会为纤维狭窄症患者提供新的治疗选择。
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引用次数: 0
Dysregulated myeloid differentiation in colitis is induced by inflammatory osteoclasts in a TNFα-dependent manner. 炎性破骨细胞以 TNFα 依赖性方式诱导结肠炎中髓质分化失调。
IF 7.9 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.mucimm.2024.09.005
Maria-Bernadette Madel, Lidia Ibáñez, Thomas Ciucci, Julia Halper, Antoine Boutin, Ghada Beldi, Alice C Lavanant, Henri-Jean Garchon, Matthieu Rouleau, Christopher G Mueller, Laurent Peyrin-Biroulet, David Moulin, Claudine Blin-Wakkach, Abdelilah Wakkach

Inflammatory bowel disease (IBD) is characterized by very severe intestinal inflammation associated with extra-intestinal manifestations. One of the most critical ones is bone destruction, which remains a major cause of morbidity and a risk factor for osteopenia and osteoporosis in IBD patients. In various mouse models of IBD, we and other have demonstrated concomitant bone loss due to a significant increase in osteoclast activity. Besides bone resorption, osteoclasts are known to control hematopoietic niches in vivo and modulate inflammatory responses in vitro, suggesting they may participate in chronic inflammation in vivo. Here, using different models of colitis, we showed that osteoclast inhibition significantly reduced disease severity and that induction of osteoclast differentiation by RANKL contributed to disease worsening. Our results demonstrate a direct link between osteoclast activity and myeloid cell accumulation in the intestine during colitis. RNAseq analysis of osteoclasts from colitic mice revealed overexpression of genes involved in the remodeling of hematopoietic stem cell niches. We also demonstrated that osteoclasts induced hematopoietic progenitor proliferation accompanied by a myeloid skewing in the early phases of colitis, which was confirmed in a model of RANKL-induced osteoclastogenesis. Mechanistically, inhibition of TNF-α reduced the induction of myeloid skewing by OCL both in vitro and in vivo. Lastly, we observed that osteoclastic activity and the proportion of myeloid cells in the blood are positively correlated in patients with Crohn's disease. Collectively, our results shed light on a new role of osteoclasts in colitis in vivo, demonstrating they exert their colitogenic activity through an early action on hematopoiesis, leading to an increase in myelopoiesis sustaining gut inflammation.

炎症性肠病(IBD)的特点是非常严重的肠道炎症,并伴有肠道外表现。其中最关键的是骨质破坏,它仍然是 IBD 患者发病的主要原因,也是骨质疏松和骨质疏松症的危险因素。在各种 IBD 小鼠模型中,我们和其他研究人员已经证实,由于破骨细胞活性显著增加,骨质会同时流失。除了骨吸收外,破骨细胞还能控制体内造血龛和调节体外炎症反应,这表明它们可能参与体内慢性炎症。在这里,我们利用不同的结肠炎模型,发现抑制破骨细胞可显著减轻疾病的严重程度,而 RANKL 诱导破骨细胞分化则会导致疾病恶化。我们的研究结果表明,在结肠炎期间,破骨细胞的活性与肠道中髓样细胞的积聚之间存在直接联系。对结肠炎小鼠破骨细胞的 RNAseq 分析显示,参与造血干细胞龛重塑的基因过度表达。我们还证明,在结肠炎的早期阶段,破骨细胞诱导造血祖细胞增殖,并伴有骨髓偏斜,这在RANKL诱导的破骨细胞生成模型中得到了证实。从机制上讲,抑制 TNF-α 可减少 OCL 在体外和体内诱导的骨髓偏斜。最后,我们观察到,克罗恩病患者的破骨细胞活性与血液中髓样细胞的比例呈正相关。总之,我们的研究结果揭示了破骨细胞在体内结肠炎中的新作用,证明它们通过早期对造血的作用来发挥其结肠致病活性,导致维持肠道炎症的骨髓造血增加。
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引用次数: 0
Combined plasma protein and memory T cell profiling discern IBD-patient-immunotypes related to intestinal disease and treatment outcomes. 结合血浆蛋白和Tmem图谱识别与肠道疾病和治疗效果相关的IBD患者免疫分型:简短标题:确定 CD 和 UC 的免疫分型。
IF 7.9 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.mucimm.2024.09.004
Maud Heredia, Mohammed Charrout, Renz C W Klomberg, Martine A Aardoom, Maria M E Jongsma, Polychronis Kemos, Danielle H Hulleman-van Haaften, Bastiaan Tuk, Lisette A van Berkel, Brenda Bley Folly, Beatriz Calado, Sandrine Nugteren, Ytje Simons-Oosterhuis, Michail Doukas, Mathijs A Sanders, Gregory van Beek, Frank M Ruemmele, Nicholas M Croft, Ahmed Mahfouz, Marcel J T Reinders, Johanna C Escher, Lissy de Ridder, Janneke N Samsom

Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-naïve pediatric IBD (Crohn's disease, CD: n = 62; ulcerative colitis, UC: n = 20; age-matched controls n = 43), and after 10-12 weeks' induction therapy. At diagnosis, plasma protein profiles unveiled two UC and three CD clusters with distinct disease courses. UC patients displayed unchanged circulating Tmem, while CD exhibited increased frequencies of gut-homing ex-Th17, known for high IFN-γ production. UC#2 had elevated Th17/neutrophil-pathway-related proteins and severe disease, with higher endoscopic and histological damage and Th17/neutrophil infiltration. Although both UC#1 and UC#2 responded to therapy, UC#2 required earlier immunomodulation. CD#3 had lower plasma protein concentrations, especially IFN-γ pathway proteins, fewer gut-homing ex-Th17 and clinically milder disease, confirmed by intestinal gene expression. CD#1 and CD#2 had comparably high Th1-related immune profiles, but CD#1 exhibited higher concentrations of proteins previously associated with poorer prognosis. Both CD clusters responded to induction therapy, with similar one-year outcomes. This study highlights feasibility of discriminating patient-specific immunotypes in IBD, advancing our understanding of immune pathogenesis, needed for tailored treatment strategies.

炎症性肠病(IBD)的慢性化源于记忆性 T 辅助细胞(Tmem)的重新激活。确定患者的特异性免疫分型对定制治疗至关重要。我们进行了一项综合研究,将循环免疫蛋白和循环 Tmem 与肠组织组织学和 mRNA 分析结合起来,研究对象是治疗前和 10-12 周诱导治疗后的小儿 IBD 患者(克罗恩病,CD:62 人;溃疡性结肠炎,UC:20 人;年龄匹配的对照组,43 人)。确诊时,血浆蛋白图谱显示有两组 UC 和三组 CD 患者的病程各不相同。UC患者的循环Tmem没有变化,而CD患者的肠道归巢外Th17(以产生大量IFN-γ而闻名)频率增加。UC#2的Th17/中性粒细胞通路相关蛋白升高,病情严重,内镜和组织学损伤加重,Th17/中性粒细胞浸润增加。虽然 UC#1 和 UC#2 都对治疗有反应,但 UC#2 需要更早地进行免疫调节。CD#3的血浆蛋白浓度较低,尤其是IFN-γ通路蛋白,肠道归巢的外Th17较少,临床病情较轻,肠道基因表达证实了这一点。CD#1和CD#2的Th1相关免疫特征相当高,但CD#1表现出较高的蛋白质浓度,而这些蛋白质以前与预后较差有关。两个CD群对诱导治疗都有反应,一年的预后相似。这项研究凸显了鉴别 IBD 患者特异性免疫分型的可行性,促进了我们对免疫发病机制的了解,而这正是定制治疗策略所需要的。
{"title":"Combined plasma protein and memory T cell profiling discern IBD-patient-immunotypes related to intestinal disease and treatment outcomes.","authors":"Maud Heredia, Mohammed Charrout, Renz C W Klomberg, Martine A Aardoom, Maria M E Jongsma, Polychronis Kemos, Danielle H Hulleman-van Haaften, Bastiaan Tuk, Lisette A van Berkel, Brenda Bley Folly, Beatriz Calado, Sandrine Nugteren, Ytje Simons-Oosterhuis, Michail Doukas, Mathijs A Sanders, Gregory van Beek, Frank M Ruemmele, Nicholas M Croft, Ahmed Mahfouz, Marcel J T Reinders, Johanna C Escher, Lissy de Ridder, Janneke N Samsom","doi":"10.1016/j.mucimm.2024.09.004","DOIUrl":"10.1016/j.mucimm.2024.09.004","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-naïve pediatric IBD (Crohn's disease, CD: n = 62; ulcerative colitis, UC: n = 20; age-matched controls n = 43), and after 10-12 weeks' induction therapy. At diagnosis, plasma protein profiles unveiled two UC and three CD clusters with distinct disease courses. UC patients displayed unchanged circulating Tmem, while CD exhibited increased frequencies of gut-homing ex-Th17, known for high IFN-γ production. UC#2 had elevated Th17/neutrophil-pathway-related proteins and severe disease, with higher endoscopic and histological damage and Th17/neutrophil infiltration. Although both UC#1 and UC#2 responded to therapy, UC#2 required earlier immunomodulation. CD#3 had lower plasma protein concentrations, especially IFN-γ pathway proteins, fewer gut-homing ex-Th17 and clinically milder disease, confirmed by intestinal gene expression. CD#1 and CD#2 had comparably high Th1-related immune profiles, but CD#1 exhibited higher concentrations of proteins previously associated with poorer prognosis. Both CD clusters responded to induction therapy, with similar one-year outcomes. This study highlights feasibility of discriminating patient-specific immunotypes in IBD, advancing our understanding of immune pathogenesis, needed for tailored treatment strategies.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dissecting the metabolic signaling pathways by which microbial molecules drive the differentiation of regulatory B cells. 剖析微生物分子驱动调节性 B 细胞分化的代谢信号通路。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-16 DOI: 10.1016/j.mucimm.2024.09.003
Maik Luu,Felix F Krause,Heide Monning,Anne Wempe,Hanna Leister,Lisa Mainieri,Sarah Staudt,Kai Ziegler-Martin,Kira Mangold,Nora Kappelhoff,Yoav D Shaul,Stephan Göttig,Carlos Plaza-Sirvent,Leon N Schulte,Isabelle Bekeredjian-Ding,Ingo Schmitz,Ulrich Steinhoff,Alexander Visekruna
The host-microbiome axis has been implicated in promoting anti-inflammatory immune responses. Yet, the underlying molecular mechanisms of commensal-mediated IL-10 production by regulatory B cells (Bregs) are not fully elucidated. Here, we demonstrate that bacterial CpG motifs trigger the signaling downstream of TLR9 promoting IκBNS-mediated expression of Blimp-1, a transcription regulator of IL-10. Surprisingly, this effect was counteracted by the NF-κB transcription factor c-Rel. A functional screen for intestinal bacterial species identified the commensal Clostridium sporogenes, secreting high amounts of short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs), as an amplifier of IL-10 production by promoting sustained mTOR signaling in B cells. Consequently, enhanced Breg functionality was achieved by combining CpG with the SCFA butyrate or the BCFA isovalerate thereby synergizing TLR- and mTOR-mediated pathways. Collectively, Bregs required two bacterial signals (butyrate and CpG) to elicit their full suppressive capacity and ameliorate T cell-mediated intestinal inflammation. Our study has dissected the molecular pathways induced by bacterial factors, which might contribute not only to better understanding of host-microbiome interactions, but also to exploration of new strategies for improvement of anti-inflammatory cellular therapy.
宿主-微生物组轴与促进抗炎免疫反应有关。然而,共生菌介导调节性 B 细胞(Bregs)产生 IL-10 的潜在分子机制尚未完全阐明。在这里,我们证明了细菌的 CpG 基序触发了 TLR9 下游的信号传导,促进了 IκBNS 介导的 Blimp-1 (IL-10 的转录调节因子)的表达。令人惊讶的是,这种效应被 NF-κB 转录因子 c-Rel 所抵消。通过对肠道细菌种类进行功能筛选,发现共生梭状芽孢杆菌能分泌大量短链脂肪酸(SCFAs)和支链脂肪酸(BCFAs),通过促进 B 细胞中持续的 mTOR 信号传导来促进 IL-10 的产生。因此,通过将 CpG 与 SCFA 丁酸酯或 BCFA 异戊酸酯结合,从而协同 TLR 和 mTOR 介导的途径,可增强 Breg 的功能。总之,Bregs 需要两种细菌信号(丁酸盐和 CpG)才能激发其全部抑制能力并改善 T 细胞介导的肠道炎症。我们的研究剖析了细菌因子诱导的分子通路,这不仅有助于更好地理解宿主与微生物组的相互作用,还有助于探索改善抗炎细胞疗法的新策略。
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引用次数: 0
Controlling functional homeostasis of ileal resident macrophages by vitamin B12 during steady state and Salmonella infection in mice 维生素 B12 在小鼠稳态和沙门氏菌感染期间控制回肠常驻巨噬细胞的功能平衡
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-08 DOI: 10.1016/j.mucimm.2024.08.011
Yong Ge, Mojgan Zadeh, Cheshta Sharma, Yang-Ding Lin, Alexey A. Soshnev, Mansour Mohamadzadeh
Dietary micronutrients, particularly vitamin B12 (VB12), profoundly influence the physiological maintenance and function of intestinal cells. However, it is still unclear whether VB12 modulates the transcriptional and metabolic programming of ileal macrophages (iMacs), thereby contributing to intestinal homeostasis. Using multiomic approaches, we demonstrated that VB12 primarily supports the cell cycle activity and mitochondrial metabolism of iMacs, resulting in increased cell frequency compared to VB12 deficiency. VB12 also retained the ability to promote maintenance and metabolic regulation of iMacs during intestinal infection with Typhimurium (STm). On the contrary, depletion of iMacs by inhibiting CSF1R signaling significantly increased host susceptibility to STm and prevented VB12-mediated pathogen reduction. These results thus suggest that regulation of VB12-dependent iMacs critically controls STm expansion, which may be of new relevance to advance our understanding of this vitamin and to strategically formulate sustainable therapeutic nutritional regimens that improve human gut health.
膳食微量营养素,尤其是维生素 B12(VB12),对肠道细胞的生理维护和功能有着深远的影响。然而,VB12 是否会调节回肠巨噬细胞(iMacs)的转录和代谢程序,从而促进肠道平衡,目前仍不清楚。利用多组学方法,我们证明了 VB12 主要支持 iMacs 的细胞周期活动和线粒体代谢,从而使细胞频率比 VB12 缺乏时更高。在伤寒杆菌(STm)肠道感染期间,VB12 还能促进 iMacs 的维持和代谢调节。相反,通过抑制 CSF1R 信号来消耗 iMacs 会显著增加宿主对 STm 的易感性,并阻止 VB12 介导的病原体减少。因此,这些结果表明,依赖于 VB12 的 iMacs 的调控关键性地控制着 STm 的扩展,这可能与我们加深对这种维生素的了解以及战略性地制定改善人类肠道健康的可持续治疗营养方案有新的关系。
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引用次数: 0
The Kynurenine Pathway Regulated by Intestinal Innate Lymphoid Cells Mediates Postoperative Cognitive Dysfunction. 由肠道先天性淋巴细胞调控的犬尿氨酸通路介导术后认知功能障碍
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-07 DOI: 10.1016/j.mucimm.2024.09.002
Wan-Bing Dai,Xiao Zhang,Xu-Liang Jiang,Yi-Zhe Zhang,Ling-Ke Chen,Wei-Tian Tian,Xiao-Xin Zhou,Xiao-Yu Sun,Li-Li Huang,Xi-Yao Gu,Xue-Mei Chen,Xiao-Dan Wu,Jie Tian,Wei-Feng Yu,Lei Shen,Dian-San Su
Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication that can impair learning and memory for days, months, or even years after anesthesia/surgery. POCD is strongly associated with an altered composition of the gut microbiota (dysbiosis), but the accompanying metabolic changes and their role in gut-brain communication and POCD pathogenesis remain unclear. Here, the present study reports that anesthesia/surgery in aged mice induces elevated intestinal indoleamine 2,3-dioxygenase (IDO) activity, which shiftes intestinal tryptophan (TRP) metabolism toward more IDO-catalyzed kynurenine (KYN) and less gut bacteria-catabolized indoleacetic acid (IAA). Both anesthesia/surgery and intraperitoneal KYN administration induce increased KYN levels that correlate with impaired spatial learning and memory, whereas dietary IAA supplementation attenuates the anesthesia/surgery-induced cognitive impairment. Mechanistically, anesthesia/surgery increases the proportion of interferon-γ (IFN-γ)-producing group 1 innate lymphoid cells (ILC1) in the small intestine lamina propria and elevates intestinal IDO expression and activity, as indicated by the higher ratio of KYN to TRP. The IDO inhibitor 1-MT and antibodies targeting IFN-γ or ILCs mitigate anesthesia/surgery-induced cognitive dysfunction, suggesting that intestinal ILC1 expansion and the ensuing IFN-γ-induced IDO upregulation may be the primary pathway mediating the shift to the KYN pathway in POCD. The ILC1-KYN pathway in the intestine could be a promising therapeutic target for POCD.
术后认知功能障碍(POCD)是一种常见的神经系统并发症,可在麻醉/手术后数天、数月甚至数年内影响学习和记忆。POCD 与肠道微生物群组成的改变(菌群失调)密切相关,但伴随而来的代谢变化及其在肠脑沟通和 POCD 发病机制中的作用仍不清楚。本研究报告了老年小鼠的麻醉/手术诱导肠道吲哚胺 2,3-二氧化酶(IDO)活性升高,从而使肠道色氨酸(TRP)代谢转向更多的 IDO 催化的犬尿氨酸(KYN)和更少的肠道细菌代谢的吲哚乙酸(IAA)。麻醉/手术和腹腔注射 KYN 都会引起 KYN 水平升高,而 KYN 水平升高与空间学习和记忆受损有关,而膳食中补充 IAA 则会减轻麻醉/手术引起的认知障碍。从机理上讲,麻醉/手术增加了小肠固有层中产生干扰素-γ(IFN-γ)的第1组先天性淋巴细胞(ILC1)的比例,并提高了肠道IDO的表达和活性,KYN与TRP的比例升高就表明了这一点。IDO抑制剂1-MT和针对IFN-γ或ILC的抗体可减轻麻醉/手术诱发的认知功能障碍,这表明肠道ILC1的扩张和随之而来的IFN-γ诱导的IDO上调可能是POCD向KYN途径转变的主要介导途径。肠道中的 ILC1-KYN 通路可能是治疗 POCD 的一个很有前景的靶点。
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引用次数: 0
Dysregulated NOX1-NOS2 activity as hallmark of ileitis in mice. NOX1-NOS2 活性失调是小鼠回肠炎的标志。
IF 7.9 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-07 DOI: 10.1016/j.mucimm.2024.08.012
Julie Drieu La Rochelle, Josie Ward, Emily Stenke, Yuting Yin, Misaki Matsumoto, Richard Jennings, Gabriella Aviello, Ulla G Knaus

Inflammation of the ileum, or ileitis, is commonly caused by Crohn's disease (CD) but can also accompany ulcerative colitis (backwash ileitis), infections or drug-related damage. Oxidative tissue injury triggered by reactive oxygen species (ROS) is considered part of the ileitis etiology. However, not only elevated ROS but also permanently decreased ROS are associated with inflammatory bowel disease (IBD). While very early onset IBD (VEO-IBD) is associated with a spectrum of NOX1 variants, how NOX1 inactivation contributes to disease development remains ill-defined. Besides propagating signaling responses, NOX1 provides superoxide for peroxynitrite formation in the epithelial barrier. Here we report that NOX4, an H2O2-generating NADPH oxidase with documented tissue protective effects in the intestine and other tissues, limits the generation of ileal peroxynitrite by NOX1/NOS2. Deletion of NOX4 leads to persistent peroxynitrite excess, hyperpermeability, villus blunting, muscular hypertrophy, chemokine/cytokine upregulation and dysbiosis. Conversely, SAMP1/YitFc mice, a CD-like ileitis model, showed age-dependent NOX1/NOS2 downregulation preventing ileal peroxynitrite formation in homeostasis and LPS-induced acute inflammation. Deficiency in NOX1 correlated with the upregulation of antimicrobial peptides, suggesting that ileal peroxynitrite acts as chemical barrier and microbiota modifier in the ileum.

回肠炎症或回肠炎通常由克罗恩病(CD)引起,但也可能伴随溃疡性结肠炎(反冲洗性回肠炎)、感染或药物相关损伤。活性氧(ROS)引发的氧化性组织损伤被认为是回肠炎病因的一部分。然而,炎症性肠病(IBD)不仅与 ROS 升高有关,还与 ROS 长期减少有关。虽然极早发 IBD(VEO-IBD)与一系列 NOX1 变体有关,但 NOX1 失活如何导致疾病发展仍未明确。除了传播信号反应外,NOX1 还为上皮屏障中过亚硝酸盐的形成提供超氧化物。在这里,我们报告了 NOX4(一种产生 H2O2 的 NADPH 氧化酶,在肠道和其他组织中具有有据可查的组织保护作用)限制了 NOX1/NOS2 产生回肠过亚硝酸盐。缺失 NOX4 会导致持续的过亚硝酸盐过量、高渗透性、绒毛变钝、肌肉肥大、趋化因子/细胞因子上调和菌群失调。相反,SAMP1/YitFc 小鼠(一种类似 CD 的回肠炎模型)表现出年龄依赖性 NOX1/NOS2 下调,从而防止了在平衡状态和 LPS 诱导的急性炎症中回肠过氧亚硝酸盐的形成。NOX1 的缺失与抗菌肽的上调有关,这表明回肠过氧亚硝酸盐在回肠中起着化学屏障和微生物群调节剂的作用。
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引用次数: 0
MicroRNA-142 regulates gut associated lymphoid tissues and group 3 innate lymphoid cells. MicroRNA-142 调节肠道相关淋巴组织和第 3 组先天性淋巴细胞。
IF 7.9 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-07 DOI: 10.1016/j.mucimm.2024.09.001
Luke B Roberts, Joana F Neves, Dave C H Lee, Sara Valpione, Roser Tachó-Piñot, Jane K Howard, Matthew R Hepworth, Graham M Lord

The transcriptomic signatures that shape responses of innate lymphoid cells (ILCs) have been well characterised, however post-transcriptional mechanisms which regulate their development and activity remain poorly understood. We demonstrate that ILC groups of the intestinal lamina propria express mature forms of microRNA-142 (miR-142), an evolutionarily conserved microRNA family with several non-redundant regulatory roles within the immune system. Germline Mir142 deletion alters intestinal ILC compositions, resulting in the absence of T-bet+ populations and significant defects in the cellularity and phenotypes of ILC3 subsets including CCR6+ LTi-like ILC3s. These effects were associated with decreased pathology in an innate-immune cell driven model of colitis. Furthermore, Mir142-/- mice demonstrate defective development of gut-associated lymphoid tissues, including a complete absence of mature Peyer's patches. Conditional deletion of Mir142 in ILC3s (RorcΔMir142) supported cell-intrinsic roles for these microRNAs in establishing or maintaining cellularity and functions of LTi-like ILC3s in intestinal associated tissues. RNAseq analysis revealed several target genes and biological pathways potentially regulated by miR-142 microRNAs in these cells. Finally, lack of Mir142 in ILC3 led to elevated IL-17A production. These data broaden our understanding of immune system roles of miR-142 microRNAs, identifying these molecules as critical post-transcriptional regulators of ILC3s and intestinal mucosal immunity.

影响先天性淋巴细胞(ILCs)反应的转录组特征已经得到了很好的描述,但对其发育和活性的转录后调控机制仍然知之甚少。我们证明肠固有层的 ILC 群表达成熟形式的 microRNA-142 (miR-142),miR-142 是一个进化保守的 microRNA 家族,在免疫系统中具有多种非冗余的调控作用。种系Mir142缺失会改变肠道ILC的组成,导致T-bet+群体缺失,ILC3亚群(包括CCR6+ LTi-like的ILC3)的细胞性和表型出现显著缺陷。这些影响与先天性免疫细胞驱动的结肠炎模型中病理变化的减少有关。此外,Mir142-/-小鼠表现出肠道相关淋巴组织发育缺陷,包括完全没有成熟的佩耶氏斑块。在 ILC3s(RorcΔMir142)中有条件地缺失 Mir142 支持这些 microRNA 在肠道相关组织中建立或维持 LTi-like ILC3s 细胞性和功能的细胞内在作用。RNAseq 分析揭示了这些细胞中可能受 miR-142 microRNAs 调控的几个靶基因和生物通路。最后,ILC3 中缺少 Mir142 会导致 IL-17A 生成增加。这些数据拓宽了我们对 miR-142 microRNA 在免疫系统中作用的认识,确定了这些分子是 ILC3 和肠粘膜免疫的关键转录后调控因子。
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引用次数: 0
Dietary fiber promotes antigen presentation on intestinal epithelial cells and development of small intestinal CD4+CD8αα+ intraepithelial T cells. 膳食纤维可促进肠上皮细胞的抗原呈递和小肠 CD4+CD8αα+ 上皮内 T 细胞的发育。
IF 7.9 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.mucimm.2024.08.010
Naomi Rodriguez-Marino, Charlotte J Royer, Dormarie E Rivera-Rodriguez, Emma Seto, Isabelle Gracien, Rheinallt M Jones, Christopher D Scharer, Adam D Gracz, Luisa Cervantes-Barragan

The impact of dietary fiber on intestinal T cell development is poorly understood. Here we show that a low fiber diet reduces MHC-II antigen presentation by small intestinal epithelial cells (IECs) and consequently impairs development of CD4+CD8αα+ intraepithelial lymphocytes (DP IELs) through changes to the microbiota. Dietary fiber supports colonization by Segmented Filamentous Bacteria (SFB), which induces the secretion of IFNγ by type 1 innate lymphoid cells (ILC1s) that lead to MHC-II upregulation on IECs. IEC MHC-II expression caused either by SFB colonization or exogenous IFNγ administration induced differentiation of DP IELs. Finally, we show that a low fiber diet promotes overgrowth of Bifidobacterium pseudolongum, and that oral administration of B. pseudolongum reduces SFB abundance in the small intestine. Collectively we highlight the importance of dietary fiber in maintaining the balance among microbiota members that allow IEC MHC-II antigen presentation and define a mechanism of microbiota-ILC-IEC interactions participating in the development of intestinal intraepithelial T cells.

人们对膳食纤维对肠道 T 细胞发育的影响知之甚少。在这里,我们发现低纤维饮食会减少小肠上皮细胞(IECs)的MHC-II抗原呈递,从而通过微生物群的变化损害CD4+CD8αα+上皮内淋巴细胞(DP IELs)的发育。膳食纤维支持分节丝状菌(SFB)定植,SFB 诱导 1 型先天性淋巴细胞(ILC1s)分泌 IFNγ,导致 IEC 上的 MHC-II 上调。由 SFB 定殖或外源 IFNγ 引起的 IEC MHC-II 表达可诱导 DP IELs 分化。最后,我们发现低纤维饮食会促进假龙双歧杆菌的过度生长,而口服假龙双歧杆菌会降低小肠中 SFB 的丰度。总之,我们强调了膳食纤维在维持微生物群成员之间的平衡方面的重要性,这种平衡使 IEC MHC-II 抗原递呈成为可能,并确定了微生物群-ILC-IEC 相互作用参与肠上皮内 T 细胞发育的机制。
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引用次数: 0
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Mucosal Immunology
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