Jackson Jazmyne L, Saxena Reshu, Murray Mary Grace, Staub Abigail J, Klochkova Alena, Bordner Travis H, Worrell Courtney, Fuller Annie D, Crespo John M, Klein-Szanto Andres J, Elrod John, Karakasheva Tatiana A, Ruffner Melanie, Muir Amanda B, Whelan Kelly A
bioRxiv. 2025 Apr 2:2025.04.02.646853. doi: 10.1101/2025.04.02.646853.
BACKGROUND: The significance of mitochondria in EoE pathobiology remains elusive. OBJECTIVE: To determine the impact of EoE inflammatory mediators upon mitochondrial biology in esophageal epithelium, the mechanisms mediating these effects, and their functional significance to EoE pathobiology. METHODS: Mitochondria were evaluated in human biopsies, MC903/Ovalbumin-induced murine EoE, and human esophageal keratinocytes. Esophageal keratinocytes were treated with EoE-relevant cytokines and JAK/STAT inhibitor ruxolitinib. To deplete mitochondria, 3D organoids generated from mice were subjected to Cre or siRNA against Transcription factor A, mitochondria (TFAM) was transfected into esophageal keratinocytes. Mitochondrial respiration, membrane potential, and superoxide levels were measured. RESULTS: We find evidence of increased mitochondria in esophageal epithelium of patients with EoE and mice with EoE-like inflammation. In esophageal keratinocytes, IL-4 and IL-13 increase mitochondrial mass. IL-13 increases mitochondrial biogenesis in a JAK/STAT-dependent manner. In 3D organoids, IL-13 limits squamous cell differentiation (SCD), and this is blunted upon TFAM depletion. IL-13 decreases mitochondrial respiration and superoxide level, although mitochondria remain intact. IL-13-mediated suppression of superoxide was abrogated upon TFAM depletion in esophageal keratinocytes. CONCLUSIONS: We report that increased mitochondrial mass is a feature of EoE. Among EoE-relevant cytokines, IL-13 is the primary driver of increased mitochondrial mass in esophageal keratinocytes by promoting mitochondrial biogenesis in a JAK/STAT-dependent manner. IL-13-mediated accumulation of mitochondria impairs SCD in esophageal keratinocytes and also suppresses oxidative stress, a factor that is known to induce SCD. These findings identify a novel mechanism through which IL-13 promotes EoE-associated epithelial remodeling. CLINICAL IMPLICATION: These findings further lay a foundation for exploration of level of esophageal epithelial mitochondria as a predictive biomarker for response to dupilumab. CAPSULE SUMMARY: IL-13 promotes mitochondrial biogenesis in esophageal epithelium, contributing to impaired squamous cell differentiation.
背景：线粒体在嗜酸性食管炎（EoE）病理生物学中的意义仍不明确。 目的：确定EoE炎症介质对食管上皮中线粒体生物学的影响、介导这些作用的机制及其对EoE病理生物学的功能意义。 方法：在人活检组织、MC903/卵清蛋白诱导的小鼠EoE模型以及人食管角质形成细胞中评估线粒体。用与EoE相关的细胞因子和JAK/STAT抑制剂鲁索替尼处理食管角质形成细胞。为了耗尽线粒体，对从小鼠产生的3D类器官进行针对线粒体转录因子A（TFAM）的Cre或siRNA处理，并将TFAM转染到食管角质形成细胞中。测量线粒体呼吸、膜电位和超氧化物水平。 结果：我们发现EoE患者和患有EoE样炎症的小鼠的食管上皮中线粒体增加的证据。在食管角质形成细胞中，白细胞介素-4（IL-4）和白细胞介素-13（IL-13）增加线粒体质量。IL-13以JAK/STAT依赖的方式增加线粒体生物合成。在3D类器官中，IL-13限制鳞状细胞分化（SCD），而在TFAM耗尽后这种作用减弱。IL-13降低线粒体呼吸和超氧化物水平，尽管线粒体保持完整。在食管角质形成细胞中，TFAM耗尽后，IL-13介导的超氧化物抑制作用被消除。 结论：我们报告线粒体质量增加是EoE的一个特征。在与EoE相关的细胞因子中，IL-13是食管角质形成细胞中线粒体质量增加的主要驱动因素，它通过以JAK/STAT依赖的方式促进线粒体生物合成来实现。IL-13介导的线粒体积累损害食管角质形成细胞中的SCD，并且还抑制氧化应激，氧化应激是已知诱导SCD的一个因素。这些发现确定了IL-13促进EoE相关上皮重塑的一种新机制。 临床意义：这些发现进一步为探索食管上皮线粒体水平作为对度普利尤单抗反应的预测生物标志物奠定了基础。 总结：IL-13促进食管上皮中的线粒体生物合成，导致鳞状细胞分化受损。
Cochrane Database Syst Rev. 2017-9-21
Cochrane Database Syst Rev. 2020-9-14
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