Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration

Aymeric Silvin; Stefan Uderhardt; Cecile Piot; Sandro Da Mesquita; Katharine Yang; Laufey Geirsdottir; Kevin Mulder; David Eyal; Zhaoyuan Liu; Cecile Bridlance; Morgane Sonia Thion; Xiao Meng Zhang; Wan Ting Kong; Marc Deloger; Vasco Fontes; Assaf Weiner; Rachel Ee; Regine Dress; Jing Wen Hang; Akhila Balachander; Svetoslav Chakarov; Benoit Malleret; Garett Dunsmore; Olivier Cexus; Jinmiao Chen; Sonia Garel; Charles Antoine Dutertre; Ido Amit; Jonathan Kipnis; Florent Ginhoux

doi:10.1016/j.immuni.2022.07.004

Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration

Aymeric Silvin, Stefan Uderhardt, Cecile Piot, Sandro Da Mesquita, Katharine Yang, Laufey Geirsdottir, Kevin Mulder, David Eyal, Zhaoyuan Liu, Cecile Bridlance, Morgane Sonia Thion, Xiao Meng Zhang, Wan Ting Kong, Marc Deloger, Vasco Fontes, Assaf Weiner, Rachel Ee, Regine Dress, Jing Wen Hang, Akhila BalachanderSvetoslav Chakarov, Benoit Malleret, Garett Dunsmore, Olivier Cexus, Jinmiao Chen, Sonia Garel, Charles Antoine Dutertre, Ido Amit, Jonathan Kipnis, Florent Ginhoux

Research output: Contribution to journal › Article › peer-review

155 Scopus citations

Abstract

Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer's disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.

Original language	English
Pages (from-to)	1448-1465.e6
Journal	Immunity
Volume	55
Issue number	8
DOIs	https://doi.org/10.1016/j.immuni.2022.07.004
State	Published - Aug 9 2022

Keywords

Alzheimer's disease
aging
disease inflammatory macrophages
disease-associated microglia
macrophage
microglia
neurodegeneration

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10.1016/j.immuni.2022.07.004

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Silvin, A., Uderhardt, S., Piot, C., Da Mesquita, S., Yang, K., Geirsdottir, L., Mulder, K., Eyal, D., Liu, Z., Bridlance, C., Thion, M. S., Zhang, X. M., Kong, W. T., Deloger, M., Fontes, V., Weiner, A., Ee, R., Dress, R., Hang, J. W., ... Ginhoux, F. (2022). Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration. Immunity, 55(8), 1448-1465.e6. https://doi.org/10.1016/j.immuni.2022.07.004

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title = "Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration",

abstract = "Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer's disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.",

keywords = "Alzheimer's disease, aging, disease inflammatory macrophages, disease-associated microglia, macrophage, microglia, neurodegeneration",

author = "Aymeric Silvin and Stefan Uderhardt and Cecile Piot and {Da Mesquita}, Sandro and Katharine Yang and Laufey Geirsdottir and Kevin Mulder and David Eyal and Zhaoyuan Liu and Cecile Bridlance and Thion, {Morgane Sonia} and Zhang, {Xiao Meng} and Kong, {Wan Ting} and Marc Deloger and Vasco Fontes and Assaf Weiner and Rachel Ee and Regine Dress and Hang, {Jing Wen} and Akhila Balachander and Svetoslav Chakarov and Benoit Malleret and Garett Dunsmore and Olivier Cexus and Jinmiao Chen and Sonia Garel and Dutertre, {Charles Antoine} and Ido Amit and Jonathan Kipnis and Florent Ginhoux",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = aug,

day = "9",

doi = "10.1016/j.immuni.2022.07.004",

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Silvin, A, Uderhardt, S, Piot, C, Da Mesquita, S, Yang, K, Geirsdottir, L, Mulder, K, Eyal, D, Liu, Z, Bridlance, C, Thion, MS, Zhang, XM, Kong, WT, Deloger, M, Fontes, V, Weiner, A, Ee, R, Dress, R, Hang, JW, Balachander, A, Chakarov, S, Malleret, B, Dunsmore, G, Cexus, O, Chen, J, Garel, S, Dutertre, CA, Amit, I, Kipnis, J & Ginhoux, F 2022, 'Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration', Immunity, vol. 55, no. 8, pp. 1448-1465.e6. https://doi.org/10.1016/j.immuni.2022.07.004

TY - JOUR

T1 - Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration

AU - Silvin, Aymeric

AU - Uderhardt, Stefan

AU - Piot, Cecile

AU - Da Mesquita, Sandro

AU - Yang, Katharine

AU - Geirsdottir, Laufey

AU - Mulder, Kevin

AU - Eyal, David

AU - Liu, Zhaoyuan

AU - Bridlance, Cecile

AU - Thion, Morgane Sonia

AU - Zhang, Xiao Meng

AU - Kong, Wan Ting

AU - Deloger, Marc

AU - Fontes, Vasco

AU - Weiner, Assaf

AU - Ee, Rachel

AU - Dress, Regine

AU - Hang, Jing Wen

AU - Balachander, Akhila

AU - Chakarov, Svetoslav

AU - Malleret, Benoit

AU - Dunsmore, Garett

AU - Cexus, Olivier

AU - Chen, Jinmiao

AU - Garel, Sonia

AU - Dutertre, Charles Antoine

AU - Amit, Ido

AU - Kipnis, Jonathan

AU - Ginhoux, Florent

PY - 2022/8/9

Y1 - 2022/8/9

N2 - Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer's disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.

AB - Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer's disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.

KW - Alzheimer's disease

KW - aging

KW - disease inflammatory macrophages

KW - disease-associated microglia

KW - macrophage

KW - microglia

KW - neurodegeneration

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U2 - 10.1016/j.immuni.2022.07.004

DO - 10.1016/j.immuni.2022.07.004

M3 - Article

C2 - 35931085

AN - SCOPUS:85135890762

SN - 1074-7613

VL - 55

SP - 1448-1465.e6

JO - Immunity

JF - Immunity

IS - 8

ER -

Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration

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