DARC shuttles inflammatory chemokines across the blood–brain barrier during autoimmune central nervous system inflammation

Minten, Carsten; Alt, Carsten; Gentner, Melanie; Frei, Elisabeth; Deutsch, Urban; Lyck, Ruth; Schaeren‐Wiemers, Nicole; Rot, Antal; Engelhardt, Britta

doi:10.1093/brain/awu045

Cited by 60 publications

(75 citation statements)

References 55 publications

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“…Our analysis of restricted venular DARC expression is consistent with previous reports that have shown DARC + V-ECs in PLNs, MLNs, and brain [15, 17]. In addition, we report that DARC is also a venule-specific marker in many other murine tissues that had not been examined previously, including the skin, BM, adipose tissue, cremaster muscle, bladder, conjunctival vessels, small intestine, colon, Peyer’s patches, thymus, and pancreas.…”

Section: Discussionsupporting

confidence: 92%

Differential DARC/ACKR1 expression distinguishes venular from non-venular endothelial cells in murine tissues

et al. 2017

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BackgroundIntravascular leukocyte recruitment in most vertebrate tissues is restricted to postcapillary and collecting venules, whereas capillaries and arterioles usually support little or no leukocyte adhesion. This segmental restriction is thought to be mediated by endothelial, rather than hemodynamic, differences. The underlying mechanisms are largely unknown, in part because effective tools to distinguish, isolate, and analyze venular endothelial cells (V-ECs) and non-venular endothelial cells (NV-ECs) have been unavailable. We hypothesized that the atypical chemokine receptor DARC (Duffy Antigen Receptor for Chemokines, a.k.a. ACKR1 or CD234) may distinguish V-ECs versus NV-ECs in mice.MethodsWe generated a rat-anti-mouse monoclonal antibody (MAb) that specifically recognizes the erythroid and endothelial forms of native, surface-expressed DARC. Using this reagent, we characterized DARC expression and distribution in the microvasculature of murine tissues. ResultsDARC was exquisitely restricted to post-capillary and small collecting venules and completely absent from arteries, arterioles, capillaries, veins, and most lymphatics in every tissue analyzed. Accordingly, intravital microscopy showed that adhesive leukocyte-endothelial interactions were restricted to DARC+ venules. DARC was detectable over the entire circumference of V-ECs, but was more concentrated at cell-cell junctions. Analysis of single-cell suspensions suggested that the frequency of V-ECs among the total microvascular EC pool varies considerably between different tissues.ConclusionsImmunostaining of endothelial DARC allows the identification and isolation of intact V-ECs from multiple murine tissues. This strategy may be useful to dissect the mechanisms underlying segmental microvascular specialization in healthy and diseased tissues and to characterize the role of EC subsets in tissue-homeostasis, immune surveillance, infection, inflammation, and malignancies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0381-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Differential DARC/ACKR1 expression distinguishes venular from non-venular endothelial cells in murine tissues

et al. 2017

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“…The blood brain barrier is a crucial checkpoint for leukocyte entry in the CNS, and several homeostatic (CXCL12, CCL19, CCL20, CCL21) and inflammatory (CCL2, CCL5, CXCL1) chemokines are expressed on the vasculature and astrocytes within the brain parenchyma [73]. Noteworthy, all ACKRs except ACKR4 have also been found expressed at the blood brain barrier (ACKR1 [74]; ACKR2 [75,76]; ACKR3 [77,78]; ackr5 [34, 37, 79-81]). Transcript for ACKR4, whose ligands are highly expressed in the CNS, has been detected in murine brain [25], but further investigations are required to confirm its expression at the blood brain barrier.…”

Section: Expression Profiles Of Ackrsmentioning

confidence: 99%

“…ACKR2, ACKR3, ACKR4 and ackr5 share the ability to scavenge chemokines [41, 98,[125][126][127]. ACKR1 and ackr5 share the ability to transport or present (ACKR1 [58,62,74,128,129]; ackr5 [36,38,42,130]) their ligands, suggesting that these 2 mechanisms may be strictly correlated, and when expressed on erythrocytes, ACKR1 also acts as a sink/reservoir for chemokines, thus working as a chemokine "buffering" receptor [45,131]. As discussed in Signaling Properties of ACKRs, the mechanism used by a given ACKR to shape the chemokine gradient is strictly related on its trafficking properties.…”

Section: Chemokine Gradient Shapingmentioning

confidence: 99%

Overview and potential unifying themes of the atypical chemokine receptor family

Vacchini

Locati

Borroni

2016

Journal of Leukocyte Biology

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Chemokines modulate immune responses through their ability to orchestrate the migration of target cells. Chemokines directly induce cell migration through a distinct set of 7 transmembrane domain G proteincoupled receptors but are also recognized by a small subfamily of atypical chemokine receptors, characterized by their inability to support chemotactic activity. Atypical chemokine receptors are now emerging as crucial regulatory components of chemokine networks in a wide range of physiologic and pathologic contexts. Although a new nomenclature has been approved recently to reflect their functional distinction from their conventional counterparts, a systematic view of this subfamily is still missing. This review discusses their biochemical and immunologic properties to identify potential unifying themes in this emerging family.

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“…Spinal cord ECs harvested at peak of disease contained a subpopulation of approximately 30% that showed clear signs of inflammatory activation, and these cells were characterized by increased expression of GPCRs F2r and Darc. Chemokine GPCR DARC has previously been shown to be upregulated in brain ECs during neuroinflammation and to shuttle inflammatory chemokines across the blood-brain barrier (55). Activation of thrombin receptor PAR 1 , encoded by F2r, has been show to increase endothelial permeability and to enhance surface expression of adhesion molecules, thereby promoting platelet and leukocyte margination (25).…”

Section: Discussionmentioning

confidence: 99%

Single-cell profiling reveals GPCR heterogeneity and functional patterning during neuroinflammation

Tischner¹,

Grimm²,

Kaur³

et al. 2017

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DARC shuttles inflammatory chemokines across the blood–brain barrier during autoimmune central nervous system inflammation

Cited by 60 publications

References 55 publications

Differential DARC/ACKR1 expression distinguishes venular from non-venular endothelial cells in murine tissues

Differential DARC/ACKR1 expression distinguishes venular from non-venular endothelial cells in murine tissues

Overview and potential unifying themes of the atypical chemokine receptor family

Single-cell profiling reveals GPCR heterogeneity and functional patterning during neuroinflammation

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