CSF1-dependent macrophage support matrisome and epithelial stress-induced keratin remodeling in Eosinophilic esophagitis.

IF 7.9 2区 医学 Q1 IMMUNOLOGY Mucosal 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
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Abstract

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.

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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
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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来源期刊
Mucosal Immunology
Mucosal Immunology 医学-免疫学
CiteScore
16.60
自引率
3.80%
发文量
100
审稿时长
12 days
期刊介绍: Mucosal Immunology, the official publication of the Society of Mucosal Immunology (SMI), serves as a forum for both basic and clinical scientists to discuss immunity and inflammation involving mucosal tissues. It covers gastrointestinal, pulmonary, nasopharyngeal, oral, ocular, and genitourinary immunology through original research articles, scholarly reviews, commentaries, editorials, and letters. The journal gives equal consideration to basic, translational, and clinical studies and also serves as a primary communication channel for the SMI governing board and its members, featuring society news, meeting announcements, policy discussions, and job/training opportunities advertisements.
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