Liu Huan, Osterburg Andrew R, Flury Jennifer, Swank Zulma, McGraw Dennis W, Gupta Nishant, Wikenheiser-Brokamp Kathryn A, Kumar Ashish, Tazi Abdellatif, Inoue Yoshikazu, Hirose Masaki, McCormack Francis X, Borchers Michael T
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
JCI Insight. 2020 Feb 27;5(4):132048. doi: 10.1172/jci.insight.132048.
Pulmonary Langerhans cell histiocytosis (PLCH) is a rare smoking-related lung disease characterized by dendritic cell (DC) accumulation, bronchiolocentric nodule formation, and cystic lung remodeling. Approximately 50% of patients with PLCH harbor somatic BRAF-V600E mutations in cells of the myeloid/monocyte lineage. However, the rarity of the disease and lack of animal models have impeded the study of PLCH pathogenesis. Here, we establish a cigarette smoke-exposed (CS-exposed) BRAF-V600E-mutant mouse model that recapitulates many hallmark characteristics of PLCH. We show that CD11c-targeted expression of BRAF-V600E increases DC responsiveness to stimuli, including the chemokine CCL20, and that mutant cell accumulation in the lungs of CS-exposed mice is due to both increased cellular viability and enhanced recruitment. Moreover, we report that the chemokine CCL7 is secreted from DCs and human peripheral blood monocytes in a BRAF-V600E-dependent manner, suggesting a possible mechanism for recruitment of cells known to dominate PLCH lesions. Inflammatory lesions and airspace dilation in BRAF-V600E mice in response to CS are attenuated by transitioning animals to filtered air and treatment with a BRAF-V600E inhibitor, PLX4720. Collectively, this model provides mechanistic insights into the role of myelomonocytic cells and the BRAF-V600E mutation and CS exposure in PLCH pathogenesis and provides a platform to develop biomarkers and therapeutic targets.
肺朗格汉斯细胞组织细胞增多症（PLCH）是一种罕见的与吸烟相关的肺部疾病，其特征为树突状细胞（DC）积聚、以细支气管为中心的结节形成和肺囊性重塑。约50%的PLCH患者在髓系/单核细胞谱系细胞中存在体细胞BRAF-V600E突变。然而，该疾病的罕见性以及缺乏动物模型阻碍了对PLCH发病机制的研究。在此，我们建立了一种暴露于香烟烟雾（CS暴露）的BRAF-V600E突变小鼠模型，该模型概括了PLCH的许多标志性特征。我们发现，靶向CD11c表达BRAF-V600E可增加DC对包括趋化因子CCL20在内的刺激的反应性，并且CS暴露小鼠肺中突变细胞的积聚是由于细胞活力增加和募集增强所致。此外，我们报告趋化因子CCL7以BRAF-V600E依赖的方式从DC和人外周血单核细胞中分泌，这提示了一种可能的机制，用于募集已知在PLCH病变中占主导地位的细胞。将动物转移至过滤空气中并用BRAF-V600E抑制剂PLX4720治疗，可减轻BRAF-V600E小鼠对CS的炎症损伤和肺泡扩张。总体而言，该模型为髓单核细胞和BRAF-V600E突变以及CS暴露在PLCH发病机制中的作用提供了机制性见解，并为开发生物标志物和治疗靶点提供了一个平台。
