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

C. Matthias Wilk; Flurin Cathomas; Orsolya Török; Jessica Le Berichel; Matthew D. Park; Camille Bigenwald; George R. Heaton; Pauline Hamon; Leanna Troncoso; Brooks P. Scull; Diana Dangoor; Aymeric Silvin; Ryan Fleischmann; Meriem Belabed; Howard Lin; Elias Merad Taouli; Steffen Boettcher; Long Li; Antonio Aubry; Markus G. Manz; Julia K. Kofler; Zhenyu Yue; Sergio A. Lira; Florent Ginhoux; John F. Crary; Kenneth L. McClain; Jennifer L. Picarsic; Scott J. Russo; Carl E. Allen; Miriam Merad

doi:10.1016/j.immuni.2023.11.011

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

C. Matthias Wilk, Flurin Cathomas, Orsolya Török, Jessica Le Berichel, Matthew D. Park, Camille Bigenwald, George R. Heaton, Pauline Hamon, Leanna Troncoso, Brooks P. Scull, Diana Dangoor, Aymeric Silvin, Ryan Fleischmann, Meriem Belabed, Howard Lin, Elias Merad Taouli, Steffen Boettcher, Long Li, Antonio Aubry, Markus G. ManzJulia K. Kofler, Zhenyu Yue, Sergio A. Lira, Florent Ginhoux, John F. Crary, Kenneth L. McClain, Jennifer L. Picarsic, Scott J. Russo, Carl E. Allen, Miriam Merad

Résultats de recherche: Contribution à un journal › Article › Revue par des pairs

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Résumé

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.

langue originale	Anglais
Pages (de - à)	2790-2802.e6
journal	Immunity
Volume	56
Numéro de publication	12
Les DOIs	https://doi.org/10.1016/j.immuni.2023.11.011
état	Publié - 12 déc. 2023

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10.1016/j.immuni.2023.11.011

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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., ... Merad, M. (2023). Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders. Immunity, 56(12), 2790-2802.e6. https://doi.org/10.1016/j.immuni.2023.11.011

@article{67694ded78d54452b8fdf75d240d2161,

title = "Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders",

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.",

keywords = "LCH-ND, Langerhans cell histiocytosis, blood-brain barrier, histiocytic disorders, neurodegeneration, neuroinflammation",

author = "Wilk, {C. Matthias} and Flurin Cathomas and Orsolya T{\"o}r{\"o}k and {Le Berichel}, Jessica and Park, {Matthew D.} and Camille Bigenwald and Heaton, {George R.} and Pauline Hamon and Leanna Troncoso and Scull, {Brooks P.} and Diana Dangoor and Aymeric Silvin and Ryan Fleischmann and Meriem Belabed and Howard Lin and {Merad Taouli}, Elias and Steffen Boettcher and Long Li and Antonio Aubry and Manz, {Markus G.} and Kofler, {Julia K.} and Zhenyu Yue and Lira, {Sergio A.} and Florent Ginhoux and Crary, {John F.} and McClain, {Kenneth L.} and Picarsic, {Jennifer L.} and Russo, {Scott J.} and Allen, {Carl E.} and Miriam Merad",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = dec,

day = "12",

doi = "10.1016/j.immuni.2023.11.011",

language = "English",

volume = "56",

pages = "2790--2802.e6",

journal = "Immunity",

issn = "1074-7613",

number = "12",

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Wilk, CM, Cathomas, F, Török, O, Le Berichel, J, Park, MD, Bigenwald, C, Heaton, GR, Hamon, P, Troncoso, L, Scull, BP, Dangoor, D, Silvin, A, Fleischmann, R, Belabed, M, Lin, H, Merad Taouli, E, Boettcher, S, Li, L, Aubry, A, Manz, MG, Kofler, JK, Yue, Z, Lira, SA, Ginhoux, F, Crary, JF, McClain, KL, Picarsic, JL, Russo, SJ, Allen, CE & Merad, M 2023, 'Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders', Immunity, VOL. 56, Numéro 12, p. 2790-2802.e6. https://doi.org/10.1016/j.immuni.2023.11.011

TY - JOUR

T1 - Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders

AU - Wilk, C. Matthias

AU - Cathomas, Flurin

AU - Török, Orsolya

AU - Le Berichel, Jessica

AU - Park, Matthew D.

AU - Bigenwald, Camille

AU - Heaton, George R.

AU - Hamon, Pauline

AU - Troncoso, Leanna

AU - Scull, Brooks P.

AU - Dangoor, Diana

AU - Silvin, Aymeric

AU - Fleischmann, Ryan

AU - Belabed, Meriem

AU - Lin, Howard

AU - Merad Taouli, Elias

AU - Boettcher, Steffen

AU - Li, Long

AU - Aubry, Antonio

AU - Manz, Markus G.

AU - Kofler, Julia K.

AU - Yue, Zhenyu

AU - Lira, Sergio A.

AU - Ginhoux, Florent

AU - Crary, John F.

AU - McClain, Kenneth L.

AU - Picarsic, Jennifer L.

AU - Russo, Scott J.

AU - Allen, Carl E.

AU - Merad, Miriam

PY - 2023/12/12

Y1 - 2023/12/12

N2 - 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.

AB - 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.

KW - LCH-ND

KW - Langerhans cell histiocytosis

KW - blood-brain barrier

KW - histiocytic disorders

KW - neurodegeneration

KW - neuroinflammation

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U2 - 10.1016/j.immuni.2023.11.011

DO - 10.1016/j.immuni.2023.11.011

M3 - Article

AN - SCOPUS:85179473836

SN - 1074-7613

VL - 56

SP - 2790-2802.e6

JO - Immunity

JF - Immunity

IS - 12

ER -