Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells

被引：166

作者：

Lund, Harald ^{[1
]}

Pieber, Melanie ^{[1
]}

Parsa, Roham ^{[1
]}

Han, Jinming ^{[1
]}

Grommisch, David ^{[1
]}

Ewing, Ewoud ^{[2
]}

Kular, Lara ^{[2
]}

Needhamsen, Maria ^{[2
]}

Espinosa, Alexander ^{[3
]}

Nilsson, Emma ^{[4
]}

Overby, Anna K. ^{[4
]}

Butovsky, Oleg ^{[5
,6
]}

Jagodic, Maja ^{[2
]}

Zhang, Xing-Mei ^{[1
]}

Harris, Robert A. ^{[1
]}

机构：

[1] Karolinska Hosp Solna, Appl Immunol & Immunotherapy, Dept Clin Neurosci, Karolinska Inst,Ctr Mol Med, S-17176 Stockholm, Sweden

[2] Karolinska Hosp Solna, Ctr Mol Med, Karolinska Inst, Dept Clin Neurosci, S-17176 Stockholm, Sweden

[3] Karolinska Hosp Solna, Unit Rheumatol, Dept Med, Karolinska Inst,Ctr Mol Med, S-17176 Stockholm, Sweden

[4] Umea Univ, Dept Clin Microbiol, Virol, S-90185 Umea, Sweden

[5] Harvard Med Sch, Ann Romney Ctr Neurol Dis, Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA

[6] Harvard Med Sch, Brigham & Womens Hosp, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

瑞典研究理事会;

关键词：

CENTRAL-NERVOUS-SYSTEM; BONE-MARROW; MYELOID CELLS; MOLECULAR SIGNATURES; MACROPHAGE ONTOGENY; DENDRITIC CELLS; ADULT MICROGLIA; MONOCYTES; REVEALS; ORIGIN;

D O I：

10.1038/s41467-018-07295-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Circulating monocytes can compete for virtually any tissue macrophage niche and become long-lived replacements that are phenotypically indistinguishable from their embryonic counterparts. As the factors regulating this process are incompletely understood, we studied niche competition in the brain by depleting microglia with >95% efficiency using Cx3cr1(CreER/+)R26(DTA/+) mice and monitored long-term repopulation. Here we show that the microglial niche is repopulated within weeks by a combination of local proliferation of CX3CR1(+)F4/ 80(hi)Clec12a(+) microglia and infiltration of CX3CR1(+)F4/80(hi)Clec12a(+) macrophages that arise directly from Ly6C(hi) monocytes. This colonization is independent of blood brain barrier breakdown, paralleled by vascular activation, and regulated by type I interferon. Ly6C(hi) monocytes upregulate microglia gene expression and adopt microglia DNA methylation signatures, but retain a distinct gene signature from proliferating microglia, displaying altered surface marker expression, phagocytic capacity and cytokine production. Our results demonstrate that monocytes are imprinted by the CNS microenvironment but remain transcriptionally, epigenetically and functionally distinct.

引用

页数：13

共 69 条

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