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Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing mitogen-activated protein kinase (MAPK)-activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some individuals with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we showed that LCH-ND was caused by myeloid cells that were clonal with peripheral LCH cells. Circulating BRAF V600E+ myeloid cells caused the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiated into senescent, inflammatory CD11a+ macrophages that accumulated in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced peripheral inflammation, brain parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent targetable mechanisms of LCH-ND. [Display omitted] • MAPK activation in BM-derived CD11a+ macrophages drives neurodegeneration in LCH mice • Similar spatial and transcriptional patterns between mouse and human CNS LCH • LCH mice have a leaky BBB and enhanced CNS inflammation • Senolytic treatment prevents neurodegenerative phenotype in LCH mice Patients 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. [ABSTRACT FROM AUTHOR]

Summary To guide the design of immunotherapy strategies for patients with early stage lung tumors, we developed a multiscale immune profiling strategy to map the immune landscape of early lung adenocarcinoma lesions to search for tumor-driven immune changes. Utilizing a barcoding method that allows a simultaneous single-cell analysis of the tumor, non-involved lung, and blood cells, we provide a detailed immune cell atlas of early lung tumors. We show that stage I lung adenocarcinoma lesions already harbor significantly altered T cell and NK cell compartments. Moreover, we identified changes in tumor-infiltrating myeloid cell (TIM) subsets that likely compromise anti-tumor T cell immunity. Paired single-cell analyses thus offer valuable knowledge of tumor-driven immune changes, providing a powerful tool for the rational design of immune therapies. Video Abstract [ABSTRACT FROM AUTHOR]