Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207⁺ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Approximately 60% of LCH patients harbor somatic BRAFV600E mutations localizing to CD207⁺ DCs within lesions. However, the mechanisms driving BRAFV600E⁺ LCH cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal–related kinase activity induced by BRAFV600E inhibits C-C motif chemokine receptor 7 (CCR7)–mediated DC migration, trapping DCs in tissue lesions. Additionally, BRAFV600E increases expression of BCL2-like protein 1 (BCL2L1) in DCs, resulting in resistance to apoptosis. Pharmacological MAPK inhibition restores migration and apoptosis potential in a mouse LCH model, as well as in primary human LCH cells. We also demonstrate that MEK inhibitor-loaded nanoparticles have the capacity to concentrate drug delivery to phagocytic cells, significantly reducing off-target toxicity. Collectively, our results indicate that MAPK tightly suppresses DC migration and augments DC survival, rendering DCs in LCH lesions trapped and resistant to cell death.

^{朗格汉斯细胞组织细胞增生症 (LCH) 是一种炎性骨髓瘤，其特征是含有病理性 CD207 +}树突状细胞 (DC)的肉芽肿性病变，具有组成性激活的丝裂原活化蛋白激酶 (MAPK) 通路信号。大约 60% 的 LCH 患者携带定位于病灶内 CD207 ^{+ DC 的体细胞}BRAF V600E 突变。然而，驱动BRAF V600E ⁺ LCH 细胞在病变中积聚的机制仍然未知。在这里，我们显示由BRAF V600E诱导的持续细胞外信号相关激酶活性抑制 CC 基序趋化因子受体 7 (CCR7) 介导的 DC 迁移，将 DC 捕获在组织病变中。此外，BRAFV600E 增加 DC 中 BCL2 样蛋白 1 (BCL2L1) 的表达，导致细胞凋亡抵抗。药理学 MAPK 抑制可恢复小鼠 LCH 模型以及原代人 LCH 细胞中的迁移和凋亡潜力。我们还证明，载有 MEK 抑制剂的纳米颗粒具有将药物输送集中到吞噬细胞的能力，从而显着降低脱靶毒性。总的来说，我们的结果表明 MAPK 严格抑制 DC 迁移并增加 DC 存活，使 LCH 病变中的 DC 被困并抵抗细胞死亡。