Nimpong Jeanette A, Gebregziabher Wintana, Singh Udai P, Nagarkatti Prakash, Nagarkatti Mitzi, Hodge Johnie, Liu Chunming, Fan Daping, Ai Walden
Department of Biology, Chemistry and Environmental Health Science, Benedict College, 1600 Harden Street, Columbia, SC, United States.
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, United States.
Biochem Biophys Res Commun. 2017 Nov 4;493(1):598-603. doi: 10.1016/j.bbrc.2017.08.146. Epub 2017 Sep 1.
Asthma is a chronic inflammatory disease of the airways and the mechanisms are not fully understood. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of monocytes, granulocyte and myeloid cells at early stage of differentiation. They possess phenotypic plasticity and regulate airway inflammation. We recently reported that Kruppel-like factor 4 (KLF4) regulates MDSC differentiation into fibrocytes, emerging effectors in chronic inflammation. However, the role of KLF4 in asthma is not known. Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine and a key initiator of allergic airway inflammation. Given the fact that TSLP promotes Th2 cytokine production that increases MDSC differentiation into fibrocytes, we postulate that KLF4 regulates asthma in a TSLP-dependent manner. In this study, we utilized a model of allergic asthma with ovalbumin challenge (OVA). We found that upon OVA treatment the wild type mice had increased MDSC infiltration into the lung, up-regulation of KLF4 and TSLP gene expression, and higher levels of Th2 cytokines including IL4 and IL13. Consistently, lack of KLF4 expression in monocytes and lung epithelial cells resulted in decreased TSLP expression and lower levels of Th2 cytokines in mice, and fibrocyte generation was compromised. KLF4 deficiency in these cells also led to decreased airway hyperresponsiveness (AHR), a cardinal feature of asthma, as assessed by whole body plethysmography. Moreover, lung fibrosis as measured by trichome staining was attenuated and the population of CD45 + COL1A1+ fibrocytes was diminished in this setting. Together, our results suggest that KLF4 regulates asthma development in a TSLP- and fibrocyte-dependent manner.
哮喘是一种气道慢性炎症性疾病，其发病机制尚未完全明确。髓系来源的抑制性细胞（MDSCs）是一组异质性的单核细胞、粒细胞以及处于分化早期的髓系细胞。它们具有表型可塑性并可调节气道炎症。我们最近报道，Kruppel样因子4（KLF4）可调节MDSCs向纤维细胞的分化，而纤维细胞是慢性炎症中出现的效应细胞。然而，KLF4在哮喘中的作用尚不清楚。胸腺基质淋巴细胞生成素（TSLP）是一种上皮细胞来源的细胞因子，也是过敏性气道炎症的关键启动因子。鉴于TSLP可促进Th2细胞因子的产生，而Th2细胞因子会增加MDSCs向纤维细胞的分化，我们推测KLF4以TSLP依赖的方式调节哮喘。在本研究中，我们利用卵清蛋白激发（OVA）的过敏性哮喘模型。我们发现，经OVA处理后，野生型小鼠肺内MDSCs浸润增加，KLF4和TSLP基因表达上调，包括IL4和IL13在内的Th2细胞因子水平升高。同样，单核细胞和肺上皮细胞中KLF4表达缺失导致小鼠TSLP表达降低和Th2细胞因子水平降低，并且纤维细胞生成受损。这些细胞中KLF4缺乏还导致气道高反应性（AHR）降低，通过全身体积描记法评估，AHR是哮喘的一个主要特征。此外，通过苏木精染色测量的肺纤维化减轻，并且在这种情况下CD45 + COL1A1 +纤维细胞的数量减少。总之，我们的结果表明KLF4以TSLP和纤维细胞依赖的方式调节哮喘的发展。
