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Selective Chemokine Receptor Usage by Central Nervous System Myeloid Cells in CCR2-Red Fluorescent Protein Knock-In Mice
Open accessAbstract
BACKGROUND: Monocyte subpopulations distinguished by differential expression of chemokine receptors CCR2 and CX3CR1 are difficult to track in vivo, partly due to lack of CCR2 reagents. METHODOLOGY/PRINCIPAL FINDINGS: We created CCR2-red fluorescent protein (RFP) knock-in mice and crossed them with CX3CR1-GFP mice to investigate monocyte subset trafficking. In mice with experimental autoimmune encephalomyelitis, CCR2 was critical for efficient intrathecal accumulation and localization of Ly6C(hi)/CCR2(hi) monocytes. Surprisingly, neutrophils, not Ly6C(lo) monocytes, largely replaced Ly6C(hi) cells in the central nervous system of these mice. CCR2-RFP expression allowed the first unequivocal distinction between infiltrating monocytes/macrophages from resident microglia. CONCLUSION/SIGNIFICANCE: These results refine the concept of monocyte subsets, provide mechanistic insight about monocyte entry into the central nervous system, and present a novel model for imaging and quantifying inflammatory myeloid populations.
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“When F4/80+ macrophages were isolated from CNS and analyzed by flow cytometry using cells from double-heterozygous Ccr2rfp::Cx3cr1gfp mice with EAE, GFP was expressed by CD45dim/Ly6C− microglia, whereas RFP was restricted to CD45high/Ly6C+ monocytes (Saederup et al., 2010; Mizutani et al., 2012).”
From Differential roles of microglia and monocytes in the inflamed central nervous system (2014) · cites this paper as Saederup et al., 2010
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“To address the role of MDMs in demyelination at EAE onset, we investigated clinical characteristics in relation to node pathology and demyelination in Ccr2rfp/rfp::Cx3cr1gfp/+ mice in which MDMs were virtually absent from inflamed EAE tissues and replaced in large part by neutrophils (Saederup et al., 2010).”
From Differential roles of microglia and monocytes in the inflamed central nervous system (2014) · cites this paper as Saederup et al., 2010
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“CCR2+Ly6C+ cells constitute the vast majority of infiltrating monocytes at EAE onset (Saederup et al., 2010; Mizutani et al., 2012).”
From Differential roles of microglia and monocytes in the inflamed central nervous system (2014) · cites this paper as Saederup et al., 2010
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“We took advantage of ccr2RFP∷ cx3cr1GFP double heterozygous mice 35 in which adult resident microglia exhibit a ccr2RFP−/cx3cr1GFP+ pattern35, 36, whereas peripheral monocytes, which are recruited in response to inflammation, are characterized by a ccr2RFP+/cx3cr1GFP− pattern35–37.”
From Social stress induces neurovascular pathology promoting depression (2017) · cites this paper as [35]
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“Microglia were labeled using the CX3CR1+/GFP mouse line in which all microglia express EGFP under the control of fractalkine receptor, CX3CR1, expression (Figure 1, S1, and S5) (Cardona et al., 2006; Jung et al., 2000; Saederup et al., 2010).”
From Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner (2012) · cites this paper as Saederup et al., 2010
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“we found an increase in CD39−CD11bHi cells which express Ly6C (Fig. 7g) and which represent peripherally infiltrating monocytes9,12.”
From Identification of a unique TGF-β–dependent molecular and functional signature in microglia (2014) · cites this paper as [9]
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“microglia can be distinguished from monocytes using red-green mice in which microglia and monocyte-derived macrophages are labeled with CX3CR1 (GFP) and CCR2 (RFP) respectively9.”
From Identification of a unique TGF-β–dependent molecular and functional signature in microglia (2014) · cites this paper as [9]
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Metadata
- Authors
- Saederup, N., Cardona, A. E., Croft, K., Mizutani, M., Cotleur, A. C., Tsou, C.-L., Ransohoff, R. M., & Charo, I. F.
- Affiliations
- Gladstone Institutes (US)
- Cleveland Clinic (US)
- Corresponding author
- Ransohoff, Richard M.
- Charo, Israel F.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-10-27
- Volume
- 5
- Issue
- 10
- Pages
- e13693
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2965160
- OpenAlex
- W2104003768
- Cited by
- 599
- References
- 46
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 60 · 2023: 32 · 2022: 22 · 2021: 38 · 2020: 49 · 2019: 54 · 2018: 42 · 2017: 51 · 2016: 44 · 2015: 49 · 2014: 46 · 2013: 30 · 2012: 17
- FWCI
- 9.81
- Type
- journal article
- Language
- en
- Update notices
- correction (2017-04-27)
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Multiple Sclerosis Society
- Multiple Sclerosis Society
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL063894, R01HL052773, HL 52773, HL63894)
- National Institute of Neurological Disorders and Stroke (R01NS32151, R01NS032151)
- Topics
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- CCR2, CX3CR1, monocyte subsets, monocyte trafficking, experimental autoimmune encephalomyelitis, Ly6C, neutrophils, microglia, red fluorescent protein
- MeSH terms
- Red Fluorescent Protein, Animals, Central Nervous System, Luminescent Proteins, Mice, Receptors, CCR2
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