CSF1R Is Required for Differentiation and Migration of Langerhans Cells and Langerhans Cell Histiocytosis
CSF1R Is Required for Differentiation and Migration of Langerhans Cells and Langerhans Cell Histiocytosis
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DOI：
10.1158/2326-6066.cir-19-0232
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发表时间：
2020-06-01
影响因子：
10.1
通讯作者：
Vermi, William
中科院分区：
文献类型：
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作者：
Lonardi, Silvia;Scutera, Sara;Vermi, William
朗格汉斯细胞组织细胞增生症（LCH）是一种罕见的疾病，其特征是CD 1a（+）CD 207（+）LCH细胞的组织蓄积。在LCH中，在组织LCH细胞、骨髓CD 34（+）造血干细胞、循环CD 14+单核细胞和BDCA 1（+）髓样树突状细胞（DC）中检测到BRAF（V600 E）基因的体细胞突变。在克隆朗格汉斯细胞（LC）及其前体中靶向BRAF（V600 E）是肿瘤突变患者的潜在治疗选择。小鼠巨噬细胞和LC的发育受CSF 1受体（CSF 1 R）调节。在弥漫型腱鞘巨细胞瘤患者中，CSF 1 R抑制可消除肿瘤相关巨噬细胞（TAM），具有治疗效果;然而，尚未研究LC和LCH中的CSF 1 R信号传导。我们通过免疫组化和流式细胞术发现，CSF 1 R通常表达于表皮和复层上皮中的人CD 1a（+）CD 207（+）LC上。从CD 14（+）单核细胞、BDCA 1（+）DC和CD 34（+）脐带血祖细胞分化的LC表达在成熟时下调的CSF 1 R。未成熟LC向CSF 1迁移，但不向IL 34迁移。给予c-FMS/CSF 1 R激酶抑制剂GW 2580和BLZ 945显著降低了人LC迁移。在LCH临床样品中，LCH细胞（包括BRAF（V600 E）细胞）和TAM保持CSF 1 R的高表达。我们还检测到其配体，CSF 1，但不是IL 34的转录本的存在下，在所有测试的LCH的情况下。LCH中CSF 1 R和CSF 1的表达及其在LC迁移和分化中的作用表明CSF 1 R信号传导阻断是治疗LCH（包括BRAF（V600 E）和野生型疾病）的候选合理方法。
Langerhans cell histiocytosis (LCH) is a rare disorder characterized by tissue accumulation of CD1a(+)CD207(+) LCH cells. In LCH, somatic mutations of the BRAF(V600E) gene have been detected in tissue LCH cells, bone marrow CD34(+) hematopoietic stem cells, circulating CD14+ monocytes, and BDCA1(+) myeloid dendritic cells (DC). Targeting BRAF(V600E) in clonal Langerhans cells (LC) and their precursors is a potential treatment option for patients whose tumors have the mutation. The development of mouse macrophages and LCs is regulated by the CSF1 receptor (CSF1R). In patients with diffuse-type tenosynovial giant cell tumors, CSF1R inhibition depletes tumor-associated macrophages (TAM) with therapeutic efficacy; however, CSF1R signaling in LCs and LCH has not been investigated. We found through IHC and flow cytometry that CSF1R is normally expressed on human CD1a(+)CD207(+) LCs in the epidermis and stratified epithelia. LCs that were differentiated from CD14(+) monocytes, BDCA1(+) DCs, and CD34(+) cord blood progenitors expressed CSF1R that was downregulated upon maturation. Immature LCs migrated toward CSF1, but not IL34. Administration of the c-FMS/CSF1R kinase inhibitors GW2580 and BLZ945 significantly reduced human LC migration. In LCH clinical samples, LCH cells (including BRAF(V600E) cells) and TAMs retained high expression of CSF1R. We also detected the presence of transcripts for its ligand, CSF1, but not IL34, in all tested LCH cases. CSF1R and CSF1 expression in LCH, and their role in LC migration and differentiation, suggests CSF1R signaling blockade as a candidate rational approach for treatment of LCH, including the BRAF(V600E) and wild-type forms of the disease.