RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions
| Autor: | Zoi Karoulia, Marylene Leboeuf, Romain Remark, Miriam Merad, Brandon Hogstad, Poulikos I. Poulikakos, Marie-Luise Berres, Wing-hong Kwan, Howard Lin, Kenneth L. McClain, Jerry E. Chipuk, Hélène Salmon, Madhavika N. Serasinghe, Camille Bigenwald, Stefan Jordan, Veronika Kana, Karen Phaik Har Lim, Carl E. Allen, EF Brandt, Jun Tang, Tsz-Kwong Man, Willem J. M. Mulder, Rikhia Chakraborty, Samantha Baxter |
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| Přispěvatelé: | ACS - Atherosclerosis & ischemic syndromes, Medical Biochemistry |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Proto-Oncogene Proteins B-raf
0301 basic medicine MAPK/ERK pathway MAP Kinase Signaling System Immunology Apoptosis C-C chemokine receptor type 7 Article Mice 03 medical and health sciences Chemokine receptor Phagocytosis Langerhans cell histiocytosis Cell Movement medicine Animals Humans Immunology and Allergy Kinase activity Protein kinase A Dendritic cell migration Research Articles Chemistry Dendritic Cells medicine.disease 3. Good health Mice Inbred C57BL Histiocytosis Langerhans-Cell 030104 developmental biology Langerhans Cells Mutation Cancer research |
| Zdroj: | Journal of experimental medicine, 215(1), 319-336. Rockefeller University Press The Journal of Experimental Medicine |
| ISSN: | 0022-1007 |
| Popis: | Hogstad et al. show that the somatic BRAFV600E mutation in myeloid dendritic cell precursors in Langerhans cell histiocytosis promotes lesion formation through impaired dendritic cell migration and resistance to apoptosis, which can be rescued with targeted MAPK pathway inhibition. 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. |
| Databáze: | OpenAIRE |
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