A maelstrom of migrating monocytes drives neurodegeneration

Neurodegeneration is a devastating complication of Langerhans cell histiocytosis (LCH), but it is not clear how it develops. In this issue of Immunity, Wilk et al. demonstrate that circulating BRAFV600E+ myeloid cells damage the blood-brain barrier and infiltrate the brain. Dual inhibition of the MAPK and senescence pathways can block parenchymal injury, providing a potential therapeutic avenue for histiocytic neurodegeneration. Neurodegeneration is a devastating complication of Langerhans cell histiocytosis (LCH), but it is not clear how it develops. In this issue of Immunity, Wilk et al. demonstrate that circulating BRAFV600E+ myeloid cells damage the blood-brain barrier and infiltrate the brain. Dual inhibition of the MAPK and senescence pathways can block parenchymal injury, providing a potential therapeutic avenue for histiocytic neurodegeneration. Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disordersWilk et al.ImmunityDecember 12, 2023In BriefPatients with Langerhans cell histiocytosis can develop incurable neurodegeneration years after initial systemic disease. Wilk et al. found that MAPK activation in circulating myeloid cells drives a senescent and proinflammatory state that contributes to breakdown of the blood-brain barrier and accumulation of mutant macrophages in the brain. Cognitive and motor deficits can be prevented by MAPK and senolytic Bcl-xL-inhibition. Full-Text PDF