RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions Journal Article


Authors: Hogstad, B.; Berres, M. L.; Chakraborty, R.; Tang, J.; Bigenwald, C.; Serasinghe, M.; Lim, K. P. H.; Lin, H.; Man, T. K.; Remark, R.; Baxter, S.; Kana, V.; Jordan, S.; Karoulia, Z.; Kwan, W. H.; Leboeuf, M.; Brandt, E.; Salmon, H.; McClain, K.; Poulikakos, P.; Chipuk, J.; Mulder, W. J. M.; Allen, C. E.; Merad, M.
Article Title: RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions
Abstract: 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.
Keywords: signal transduction; mitogen activated protein kinase; controlled study; human tissue; protein expression; human cell; drug efficacy; drug safety; nonhuman; mouse; animal tissue; cell survival; apoptosis; enzyme inhibition; dendritic cell; clinical assessment; granulocyte macrophage colony stimulating factor; animal experiment; animal model; bim protein; caspase 3; protein bcl xl; immune response; cell migration; tumor immunity; phagocytosis; chemokine receptor ccr7; cre recombinase; tissue injury; b raf kinase; bioaccumulation; drug delivery system; phagocyte; osteoclast differentiation factor; langerhans cell histiocytosis; caspase 7; macrophage inflammatory protein 3beta; navitoclax; high density lipoprotein; trametinib; human; priority journal; article; langerin
Journal Title: Journal of Experimental Medicine
Volume: 215
Issue: 1
ISSN: 0022-1007
Publisher: Rockefeller University Press  
Date Published: 2018-01-01
Start Page: 319
End Page: 336
Language: English
DOI: 10.1084/jem.20161881
PROVIDER: scopus
PMCID: PMC5748846
PUBMED: 29263218
DOI/URL:
Notes: Article -- Export Date: 1 February 2018 -- Source: Scopus
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  1. Jun   Tang
    19 Tang