TY - JOUR
T1 - RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions
AU - Hogstad, Brandon
AU - Berres, Marie-Luise
AU - Chakraborty, Rikhia
AU - Tang, Jun
AU - Bigenwald, Camille
AU - Serasinghe, Madhavika
AU - Lim, Karen Phaik Har
AU - Lin, Howard
AU - Man, Tsz-Kwong
AU - Remark, Romain
AU - Baxter, Samantha
AU - Kana, Veronika
AU - Jordan, Stefan
AU - Karoulia, Zoi
AU - Kwan, Wing-Hong
AU - Leboeuf, Marylene
AU - Brandt, Elisa
AU - Salmon, Helene
AU - McClain, Kenneth
AU - Poulikakos, Poulikos
AU - Chipuk, Jerry
AU - Mulder, Willem J. M.
AU - Allen, Carl E.
AU - Merad, Miriam
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85039948009&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29263218
U2 - https://doi.org/10.1084/jem.20161881
DO - https://doi.org/10.1084/jem.20161881
M3 - Article
C2 - 29263218
SN - 0022-1007
VL - 215
SP - 319
EP - 336
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
ER -