Distinct myeloid population phenotypes dependent on TREM2 expression levels shape the pathology of traumatic versus demyelinating CNS disorders

Han Gao; Jiawei Di; Bettina Hjelm Clausen; Nanxiang Wang; Xizhong Zhu; Tianlun Zhao; Yanyu Chang; Mao Pang; Yang Yang; Ronghan He; Yuge Wang; Liangming Zhang; Bin Liu; Wei Qiu; Kate Lykke Lambertsen; Roberta Brambilla; Limin Rong

doi:10.1016/j.celrep.2023.112629

Distinct myeloid population phenotypes dependent on TREM2 expression levels shape the pathology of traumatic versus demyelinating CNS disorders

Han Gao^*, Jiawei Di, Bettina Hjelm Clausen, Nanxiang Wang, Xizhong Zhu, Tianlun Zhao, Yanyu Chang, Mao Pang, Yang Yang, Ronghan He, Yuge Wang, Liangming Zhang, Bin Liu, Wei Qiu, Kate Lykke Lambertsen, Roberta Brambilla^*, Limin Rong^*

^*Kontaktforfatter

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

111 Downloads (Pure)

Abstract

Triggering receptor expressed on myeloid cell 2 (TREM2) signaling often drives opposing effects in traumatic versus demyelinating CNS disorders. Here, we identify two distinct phenotypes of microglia and infiltrating myeloid populations dependent on TREM2 expression levels at the acute stage and elucidate how they mediate the opposing effects of TREM2 in spinal cord injury (SCI) versus multiple sclerosis animal models (experimental autoimmune encephalomyelitis [EAE]). High TREM2 levels sustain phagocytic microglia and infiltrating macrophages after SCI. In contrast, moderate TREM2 levels sustain immunomodulatory microglia and infiltrating monocytes in EAE. TREM2-ablated microglia (purine-sensing phenotype in SCI and reduced immunomodulatory phenotype in EAE) drive transient protection at the acute stage of both disorders, whereas reduced phagocytic macrophages and lysosome-activated monocytes lead to contrasting neuroprotective and demyelinating effects in SCI versus EAE, respectively. Our study provides comprehensive insights into the complex roles of TREM2 in myeloid populations across diverse CNS disorders, which has crucial implications in devising TREM2-targeting therapeutics.

Originalsprog	Engelsk
Artikelnummer	112629
Tidsskrift	Cell Reports
Vol/bind	42
Udgave nummer	6
Antal sider	25
ISSN	2211-1247
DOI	https://doi.org/10.1016/j.celrep.2023.112629
Status	Udgivet - 27. jun. 2023

Bibliografisk note

Funding Information:
We thank the Third Affiliated Hospital of Sun Yat-sen University Clinical Sample Bank, core cytometry, and imaging facilities. We thank the Miami Project Human Core Bank at the University of Miami Miller School of Medicine for providing postmortem human spinal cord tissues. The graphical abstract and scRNA-seq workflow illustration were made by Meile Liang. This work was supported by the National Key R&D Program of China ( 2017YFA0105403 to L.R.), the Key R&D Program of Guangdong Province ( 2019B020236002 to L.R.), the National Science Foundation for Distinguished Young Scholars of China ( 82001316 to H.G.), the China Postdoctoral Science Foundation ( 2019TQ0378 and 2019M663278 to H.G.), the Guangzhou Science and Technology Association Foundation ( X20200301007 to H.G.), the Guangzhou Science and Technology Project ( 202102080212 to M.P.), The Miami Project To Cure Paralysis (R.B.), and The Buoniconti Fund (R.B.).

Publisher Copyright:
© 2023 The Authors

Dokumenter og links

10.1016/j.celrep.2023.112629Licens: CC BY-NC-ND

Open Access VersionForlagets udgivne version, 11,6 MBLicens: CC BY-NC-ND

Citationsformater

Gao, H., Di, J., Clausen, B. H., Wang, N., Zhu, X., Zhao, T., Chang, Y., Pang, M., Yang, Y., He, R., Wang, Y., Zhang, L., Liu, B., Qiu, W., Lambertsen, K. L., Brambilla, R., & Rong, L. (2023). Distinct myeloid population phenotypes dependent on TREM2 expression levels shape the pathology of traumatic versus demyelinating CNS disorders. Cell Reports, 42(6), Artikel 112629. https://doi.org/10.1016/j.celrep.2023.112629

@article{37b1f7f795a54c56a86029707632421c,

title = "Distinct myeloid population phenotypes dependent on TREM2 expression levels shape the pathology of traumatic versus demyelinating CNS disorders",

abstract = "Triggering receptor expressed on myeloid cell 2 (TREM2) signaling often drives opposing effects in traumatic versus demyelinating CNS disorders. Here, we identify two distinct phenotypes of microglia and infiltrating myeloid populations dependent on TREM2 expression levels at the acute stage and elucidate how they mediate the opposing effects of TREM2 in spinal cord injury (SCI) versus multiple sclerosis animal models (experimental autoimmune encephalomyelitis [EAE]). High TREM2 levels sustain phagocytic microglia and infiltrating macrophages after SCI. In contrast, moderate TREM2 levels sustain immunomodulatory microglia and infiltrating monocytes in EAE. TREM2-ablated microglia (purine-sensing phenotype in SCI and reduced immunomodulatory phenotype in EAE) drive transient protection at the acute stage of both disorders, whereas reduced phagocytic macrophages and lysosome-activated monocytes lead to contrasting neuroprotective and demyelinating effects in SCI versus EAE, respectively. Our study provides comprehensive insights into the complex roles of TREM2 in myeloid populations across diverse CNS disorders, which has crucial implications in devising TREM2-targeting therapeutics.",

keywords = "CP: Immunology, CP: Neuroscience, experimental autoimmune encephalomyelitis, macrophage, microglia, monocyte, multiple sclerosis, phenotype, spinal cord injury, TREM2",

author = "Han Gao and Jiawei Di and Clausen, {Bettina Hjelm} and Nanxiang Wang and Xizhong Zhu and Tianlun Zhao and Yanyu Chang and Mao Pang and Yang Yang and Ronghan He and Yuge Wang and Liangming Zhang and Bin Liu and Wei Qiu and Lambertsen, {Kate Lykke} and Roberta Brambilla and Limin Rong",

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

year = "2023",

month = jun,

day = "27",

doi = "10.1016/j.celrep.2023.112629",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "6",

}

Gao, H, Di, J, Clausen, BH, Wang, N, Zhu, X, Zhao, T, Chang, Y, Pang, M, Yang, Y, He, R, Wang, Y, Zhang, L, Liu, B, Qiu, W, Lambertsen, KL, Brambilla, R & Rong, L 2023, 'Distinct myeloid population phenotypes dependent on TREM2 expression levels shape the pathology of traumatic versus demyelinating CNS disorders', Cell Reports, bind 42, nr. 6, 112629. https://doi.org/10.1016/j.celrep.2023.112629

TY - JOUR

T1 - Distinct myeloid population phenotypes dependent on TREM2 expression levels shape the pathology of traumatic versus demyelinating CNS disorders

AU - Gao, Han

AU - Di, Jiawei

AU - Clausen, Bettina Hjelm

AU - Wang, Nanxiang

AU - Zhu, Xizhong

AU - Zhao, Tianlun

AU - Chang, Yanyu

AU - Pang, Mao

AU - Yang, Yang

AU - He, Ronghan

AU - Wang, Yuge

AU - Zhang, Liangming

AU - Liu, Bin

AU - Qiu, Wei

AU - Lambertsen, Kate Lykke

AU - Brambilla, Roberta

AU - Rong, Limin

PY - 2023/6/27

Y1 - 2023/6/27

N2 - Triggering receptor expressed on myeloid cell 2 (TREM2) signaling often drives opposing effects in traumatic versus demyelinating CNS disorders. Here, we identify two distinct phenotypes of microglia and infiltrating myeloid populations dependent on TREM2 expression levels at the acute stage and elucidate how they mediate the opposing effects of TREM2 in spinal cord injury (SCI) versus multiple sclerosis animal models (experimental autoimmune encephalomyelitis [EAE]). High TREM2 levels sustain phagocytic microglia and infiltrating macrophages after SCI. In contrast, moderate TREM2 levels sustain immunomodulatory microglia and infiltrating monocytes in EAE. TREM2-ablated microglia (purine-sensing phenotype in SCI and reduced immunomodulatory phenotype in EAE) drive transient protection at the acute stage of both disorders, whereas reduced phagocytic macrophages and lysosome-activated monocytes lead to contrasting neuroprotective and demyelinating effects in SCI versus EAE, respectively. Our study provides comprehensive insights into the complex roles of TREM2 in myeloid populations across diverse CNS disorders, which has crucial implications in devising TREM2-targeting therapeutics.

AB - Triggering receptor expressed on myeloid cell 2 (TREM2) signaling often drives opposing effects in traumatic versus demyelinating CNS disorders. Here, we identify two distinct phenotypes of microglia and infiltrating myeloid populations dependent on TREM2 expression levels at the acute stage and elucidate how they mediate the opposing effects of TREM2 in spinal cord injury (SCI) versus multiple sclerosis animal models (experimental autoimmune encephalomyelitis [EAE]). High TREM2 levels sustain phagocytic microglia and infiltrating macrophages after SCI. In contrast, moderate TREM2 levels sustain immunomodulatory microglia and infiltrating monocytes in EAE. TREM2-ablated microglia (purine-sensing phenotype in SCI and reduced immunomodulatory phenotype in EAE) drive transient protection at the acute stage of both disorders, whereas reduced phagocytic macrophages and lysosome-activated monocytes lead to contrasting neuroprotective and demyelinating effects in SCI versus EAE, respectively. Our study provides comprehensive insights into the complex roles of TREM2 in myeloid populations across diverse CNS disorders, which has crucial implications in devising TREM2-targeting therapeutics.

KW - CP: Immunology

KW - CP: Neuroscience

KW - experimental autoimmune encephalomyelitis

KW - macrophage

KW - microglia

KW - monocyte

KW - multiple sclerosis

KW - phenotype

KW - spinal cord injury

KW - TREM2

U2 - 10.1016/j.celrep.2023.112629

DO - 10.1016/j.celrep.2023.112629

M3 - Journal article

C2 - 37289590

AN - SCOPUS:85161344753

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 6

M1 - 112629

ER -

Distinct myeloid population phenotypes dependent on TREM2 expression levels shape the pathology of traumatic versus demyelinating CNS disorders

Abstract

Bibliografisk note

Dokumenter og links

Fingeraftryk

Citationsformater