Idiopathic pulmonary fibrosis is a relentless fibrotic disease with largely unknown etiologies. Currently, the crosstalk between alveolar epithelial cells and lung-resident mesenchymal cells (especially [myo]fibroblasts) is considered to be the central pathogenesis to initiate and propagate the fibrotic process. Unfortunately, the master switch hidden in the profibrotic milieu that mediates pathogenic epithelial-mesenchymal interactions is still not well elucidated. Thus, the definite treatment target that can block and cure idiopathic pulmonary fibrosis is now lacking. Based on the previous studies, we proposed the notion that epithelium-derived triple type 2 cytokines, i.e. interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) are important pro-fibrotic mediators in idiopathic pulmonary fibrosis via two possible mechanisms: (1) paracrine pathway: directly acting on (myo)fibroblast. There may exist a structural and functional axis of (IL-25/IL-33/TSLP)⁺alveolar epithelial cells-(IL-25R/IL-33R/TSLPR)⁺ (myo)fibroblasts in fibroblastic foci of idiopathic pulmonary fibrosis patients. The crosstalk between alveolar epithelium and the adjacent mesenchymal compartment is well established by the binding of IL-25/IL-33/TSLP expressed on alveolar epithelial cells with their corresponding receptors (i.e. IL-17BR/sT2L/TSLPR) expressed on (myo)fibroblasts; (2) autocrine pathway: directly acting on alveolar epithelial cells. Alveolar epithelial cells may act as both cellular sources and targets of IL-25/IL-33/TSLP. Autocrine IL-25/IL-33/TSLP causes salient injury and phenotypic changes of alveolar epithelial cells. Thus, epithelium-derived IL-25/IL-33/TSLP may be the novel promising treatment target for the cure of idiopathic pulmonary fibrosis.

Impact statement

We suggest a novel modality in terms of IL-25/IL-33/TSLP’s pro-fibrotic role in IPF. First, IL-25/IL-33/TSLP fully activates (myo)fibroblasts in fibroblastic foci (FF) in a paracrine-dependent manner. (IL-25/IL-33/TSLP)⁺alveolar epithelial cells-(IL-25R/IL-33R/TSLPR)⁺ (myo)fibroblasts axis may contribute greatly to the abnormal epithelial-mesenchymal crosstalk and lung fibrosis. Second, IL-25/IL-33/TSLP causes significant injury and phenotypic changes of alveolar epithelial cells in an autocrine-dependent manner. By acting directly on the two most important cells in the fibrotic process, i.e. alveolar epithelial cells and (myo)fibroblasts, we support the notion that biological therapies targeting IL-25/IL-33/TSLP will shed new light on the cure of IPF patients.

中文翻译：

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IL-25 / IL-33 / TSLP会导致特发性肺纤维化：肺泡上皮细胞和（肌）成纤维细胞重要吗？

特发性肺纤维化是一种病因不明的持续性纤维化疾病。目前，肺泡上皮细胞和肺驻留间充质细胞（尤其是成肌纤维细胞）之间的串扰被认为是引发和传播纤维化过程的主要发病机理。不幸的是，仍不能很好地阐明隐藏在质子化环境中介导病原性上皮-间质相互作用的主开关。因此，现在缺乏可以阻断和治愈特发性肺纤维化的明确治疗目标。基于先前的研究，我们提出了上皮衍生的三型2细胞因子，即白介素（IL）-25，IL-33和胸腺基质淋巴细胞生成素（TSLP）是特发性肺纤维化的重要促纤维化介质，通过两个途径可能的机制：（1）旁分泌途径：直接作用于（肌）成纤维细胞。可能存在（IL-25 / IL-33 / TSLP）的结构和功能轴特发性肺纤维化患者成纤维细胞灶中的⁺肺泡上皮细胞-（IL-25R / IL-33R / TSLPR）⁺（肌）成纤维细胞 肺泡上皮细胞与相邻的间充质隔室之间的串扰是通过在肺泡上皮细胞上表达的IL-25 / IL-33 / TSLP与在（myo）上表达的相应受体（即IL-17BR / sT2L / TSLPR）的结合而建立的成纤维细胞 （2）自分泌途径：直接作用于肺泡上皮细胞。肺泡上皮细胞可能既是IL-25 / IL-33 / TSLP的细胞来源又是其靶标。自分泌IL-25 / IL-33 / TSLP会引起肺泡上皮细胞的显着损伤和表型改变。因此，上皮来源的IL-25 / IL-33 / TSLP可能是治疗特发性肺纤维化的新型有前途的治疗靶标。

影响陈述

我们建议在IL-25 / IL-33 / TSLP在IPF中的促纤维化作用方面的一种新颖的方式。首先，IL-25 / IL-33 / TSLP以旁分泌依赖性方式完全活化成纤维细胞灶（FF）中的（肌）成纤维细胞。（IL-25 / IL-33 / TSLP）⁺肺泡上皮细胞-（IL-25R / IL-33R / TSLPR）⁺（肌）成纤维细胞轴可能对异常的上皮-间充质细胞串扰和肺纤维化起很大作用。其次，IL-25 / IL-33 / TSLP以自分泌依赖的方式引起肺泡上皮细胞的严重损伤和表型变化。通过直接作用于纤维化过程中的两个最重要的细胞，即肺泡上皮细胞和（肌）成纤维细胞，我们支持针对IL-25 / IL-33 / TSLP的生物疗法将为IPF的治疗提供新的思路耐心。