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Cited by 51Histiocytic Disorders and TreatmentsNeuroinflammation and Neurodegeneration MechanismsLysosomal Storage Disorders Research

Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders

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Wilk, C. Matthias, Cathomas, Flurin, Török, Orsolya, Le Berichel, Jessica, Park, Matthew D., Bigenwald, Camille, Heaton, George R., Hamon, Pauline +22 more·2023·Immunity
DOI 10.1016/j.immuni.2023.11.011PMC PMC11587932

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Abstract

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 BRAFV600E+ 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.

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  • During aging or neurodegeneration, bone marrow-derived blood monocytes can infiltrate the brain through a disrupted blood-brain barrier and differentiate into microglia-like cells.

    “Moreover, recent studies have reported that during aging or neurodegeneration, bone marrow-derived blood monocytes can infiltrate the brain through a disrupted blood-brain barrier (BBB) and differentiate into microglia-like cells, exhibiting transcriptional and functional similarity to brain-resident microglia13–15.”

    From Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states (2026) · cites this paper as [14]

    The Discussion reports that circulating BRAFV600E+ myeloid cells entered the brain alongside BBB breakdown and differentiated into senescent CD11a+ macrophages in a model of LCH-associated neurodegeneration. It does not establish that this occurs generally during aging or neurodegeneration, or that the resulting cells are transcriptionally and functionally similar to brain-resident microglia; its extension to age-associated conditions is explicitly speculative. The indexed copy provides section labels but no page numbers. (LLM, conf=0.87)

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Authors
Wilk, C. M., Cathomas, F., Török, O., Le Berichel, J., Park, M. D., Bigenwald, C., Heaton, G. R., Hamon, P., Troncoso, L., Scull, B. P., Dangoor, D., Silvin, A., Fleischmann, R., Belabed, M., Lin, H., Merad Taouli, E., Boettcher, S., Li, L., Aubry, A., Manz, M. G., Kofler, J. K., Yue, Z., Lira, S. A., Ginhoux, F., Crary, J. F., McClain, K. L., Picarsic, J. L., Russo, S. J., Allen, C. E., & Merad, M.
Affiliations
  • Tisch Cancer Institute (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • University of Pecs (HU)
  • Inserm (FR)
  • Baylor College of Medicine (US)
  • University of Zurich (CH)
  • University of Pittsburgh (US)
  • Cincinnati Children's Hospital Medical Center (US)
Corresponding author
Allen, Carl E.
ORCID
Venue
Immunity
Publisher
Elsevier BV
Published
2023-12
Volume
56
Issue
12
Pages
2790-2802.e6
ISSN
1074-7613 (ISSN-L)
DOI
10.1016/j.immuni.2023.11.011
PMC
PMC11587932
OpenAlex
W4389615197
Cited by
51
References
6
Citations by year
2026: 15 · 2025: 20 · 2024: 15 · 2023: 1
FWCI
8.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Immunity (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • National Science Foundation
  • Leukemia and Lymphoma Society
  • Cincinnati Children's Hospital Medical Center
  • York University
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (186708, 186740)
  • Swiss Cancer Research Foundation
  • National Institutes of Health
  • NYU Grossman School of Medicine
  • National Cancer Institute (R01CA154947)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R33HD105593)
Topics
  • Health Sciences › Medicine › Physiology › Histiocytic Disorders and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
histiocytic disorders, neurodegeneration, brain infiltration, neuroinflammation, MAPK signaling, peripheral inflammation, macrophages, neuronal injury

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