Abstract
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.
Highlights
Pulmonary Langerhans cell histiocytosis (PLCH) is a rare smoking-related interstitial lung disease characterized by bronchiolocentric, Langerin+ dendritic cell (DC) accumulation and cystic remodeling of the lung
We found that CCL7, a pluripotent chemokine that can bind to receptors expressed on T cells, monocytes, eosinophils, and NK cells [30], was present at very low levels in WT mice exposed to filtered air (FA) or cigarette smoke (CS) but was increased in BRAFVE mice independent of CS exposure, suggesting a direct link between the BRAF mutation and CCL7 production (Figure 5A)
We found that BRAFVE cells produced significantly greater levels of CCL7 compared with WT and that CCL7 secretion from DCs isolated from BRAFVE mice increased following activation (Figure 5B)
Summary
Pulmonary Langerhans cell histiocytosis (PLCH) is a rare smoking-related interstitial lung disease characterized by bronchiolocentric, Langerin+ dendritic cell (DC) accumulation and cystic remodeling of the lung. The discovery over 2 decades ago of recurrent PLCH in the allografts of patients with PLCH who had undergone lung transplantation, suggested a metastatic mechanism [5]. The recent identification of several activating mutations in the mitogen-activated protein kinase (MAPK) pathway in more than 70% of patients with PLCH [6, 7] is consistent with a metastatic model and suggests that PLCH may be most appropriately classified as an inflammatory neoplastic disorder [8, 9].
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