The Chemokine Receptor D6 Constitutively Traffics to and from the Cell Surface to Internalize and Degrade Chemokines

Weber, Michele; Blair, Emma; Simpson, Clare V.; O’Hara, Maureen; Blackburn, P.E.; Rot, Antal; Graham, Gerard J.; Nibbs, Robert J. B.

doi:10.1091/mbc.e03-09-0634

Cited by 177 publications

(262 citation statements)

References 55 publications

(83 reference statements)

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“…Differently from other chemokine receptors [11], D6 expression is restricted to non-hematopoietic cells such as endothelial cells lining afferent lymphatics of skin [12], and placenta [9]. D6 binds most inflammatory, but not homeostatic, CC chemokines [9,13], internalizes constitutively [14,15] and targets the ligand for degradation [16].…”

Section: Introductionmentioning

confidence: 99%

Increased inflammation in mice deficient for the chemokine decoy receptor D6

et al. 2005

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Chemokines are chemotactic cytokines with a key role in the control of cell trafficking and positioning under homeostatic and inflammatory conditions. D6 is a promiscuous 7-transmembrane-domain receptor expressed on lymphatic vessels which recognizes most inflammatory, but not homeostatic, CC chemokines. In vitro experiments demonstrated that D6 is unable to signal after ligand engagement, and it is structurally adapted to sustain rapid and efficient ligand internalization and degradation. These unique functional properties lead to the hypothesis that D6 may be involved in the control of inflammation by acting as a decoy and scavenger receptor for inflammatory chemokines. Consistent with this hypothesis, here we report that D6 -/-mice showed an anticipated and exacerbated inflammatory response in a model of skin inflammation. Moreover, the absence of D6 resulted in increase cellularity and inflammatorychemokine levels in draining lymph nodes. Thus, D6 is a decoy receptor structurally adapted and strategically located to tune tissue inflammation and control transfer of inflammatory chemokines to draining lymph nodes.

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Section: Introductionmentioning

confidence: 99%

Increased inflammation in mice deficient for the chemokine decoy receptor D6

et al. 2005

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“…The decoy receptor D6 can bind and scavenge many CC inflammatory chemokines [34,35] such as CCL2 and CCL7. We show that the presence of CCL19 and CCL21, which are not targeted by D6, can prevent D6-mediated internalization and degradation of CCL2 and CCL7.…”

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Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Kuscher¹,

Danelon²,

Paoletti³

et al. 2009

Eur J Immunol

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The migration of monocytes to sites of inflammation is largely determined by their response to chemokines. Although the chemokine specificities and expression patterns of chemokine receptors are well defined, it is still a matter of debate how cells integrate the messages provided by different chemokines that are concomitantly produced in physiological or pathological situations in vivo. We present evidence for one regulatory mechanism of human monocyte trafficking. Monocytes can integrate stimuli provided by inflammatory chemokines in the presence of homeostatic chemokines. In particular, migration and cell responses could occur at much lower concentrations of the CCR2 agonists, in the presence of chemokines (CCL19 and CCL21) that per se do not act on monocytes. Binding studies on CCR2 1 cells showed that CCL19 and CCL21 do not compete with the CCR2 agonist CCL2. Furthermore, the presence of CCL19 or CCL21 could influence the degradation of CCL2 and CCL7 on cells expressing the decoy receptor D6. These findings disclose a new scenario to further comprehend the complexity of chemokinebased monocyte trafficking in a vast variety of human inflammatory disorders.Key words: Chemokine receptors . Chemokines . Monocytes . Synergism IntroductionConcomitant exposure to multiple chemokines, the key controllers of several immune cell functions [1], can result in enhancement of immune responses. Only recently, a broad phenomenon known as ''chemokine synergism'' has been identified [2][3][4][5][6][7][8][9][10]. Cells expressing two or more chemokine receptors, in the presence of the selective agonists, can amplify their response [2][3][4][5][6]11]. The responses mediated by low agonist concentrations can be powerfully enhanced by non-ligand chemokines in cells that do not bear the second chemokine receptor [7][8][9]. Using different biochemical approaches, these studies demonstrated that CC and CXC chemokines form heteromeric complexes, which could endow the agonist with higher activity [7,9,12].Chemokines mediate their effects through interactions with heterotrimeric G-protein-coupled receptors [13][14][15]. Most leukocytes express more than one chemokine receptor and, hence, can respond to more than one chemokine. Additionally, a great variety of in situ experiments demonstrated the concomitant expression of chemokines at target sites of leukocyte trafficking and homing [16][17][18][19][20][21].Many chemokines, apart from being agonistic for their receptors, were shown to act as natural antagonists on one or several receptors in vitro and in vivo [22]. Naturally occurring N-terminal truncations of chemokines have been identified in vivo [23] and numerous enzymes were shown to generate truncations of chemokines that render them less active or inactive [24,25]. Therefore, there are strong indications that a cell needs to 1118integrate more than one signal provided by its environment and that environmental factors other than agonists might influence their responses.Chemokine production can be either constitutive or triggere...

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“…In these cell lines, D6, unlike typical chemokine receptors (e.g. CCR5), can scavenge large quantities of extracellular chemokines (12,13). Thus, a simple model emerges whereby chemokine scavenging by D6 in vivo suppresses inflammatory leukocyte recruitment by reducing chemokine levels.…”

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confidence: 99%

“…This enables iterative rounds of chemokine internalization through clathrin-coated pits without the need for signaling, with chemokine simply associating with surface D6 molecules destined for internalization (12)(13)(14). Consequently, Ͼ95% of D6 is located in early and recycling endosomal compartments where it shows remarkable stability, presumably by avoiding transit to lysosomes (12). D6 trafficking differs from signaling-competent chemokine receptors (and most other 7TMRs) that typically reside at the cell surface and become rapidly internalized only after activation by ligand.…”

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Multiple Roles for the C-terminal Tail of the Chemokine Scavenger D6

McCulloch¹,

Morrow²,

Milasta

et al. 2008

Journal of Biological Chemistry

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D6 is a heptahelical receptor that suppresses inflammation and tumorigenesis by scavenging extracellular pro-inflammatory CC chemokines. Previous studies suggested this is dependent on constitutive trafficking of stable D6 protein to and from the cell surface via recycling endosomes. By internalizing chemokine each time it transits the cell surface, D6 can, over time, remove large quantities of these inflammatory mediators. We have investigated the role of the conserved 58-amino acid C terminus of human D6, which, unlike the rest of the protein, shows no clear homology to other heptahelical receptors. We show that, in human HEK293 cells, a serine cluster in this region controls the constitutive phosphorylation, high stability, and intracellular trafficking itinerary of the receptor and drives green fluorescent protein-tagged ␤-arrestins to membranes at, and near, the cell surface. Unexpectedly, however, these properties, and the last 44 amino acids of the C terminus, are dispensable for D6 internalization and effective scavenging of the chemokine CCL3. Even in the absence of the last 58 amino acids, D6 still initially internalizes CCL3 but, surprisingly, exposure to ligand inhibits subsequent CCL3 uptake by this mutant. Progressive scavenging is therefore abrogated. We conclude that the heptahelical body of D6 on its own can engage the endocytotic machinery of HEK293 cells but that the C terminus is indispensable for scavenging because it prevents initial chemokine engagement of D6 from inhibiting subsequent chemokine uptake.

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The Chemokine Receptor D6 Constitutively Traffics to and from the Cell Surface to Internalize and Degrade Chemokines

Cited by 177 publications

References 55 publications

Increased inflammation in mice deficient for the chemokine decoy receptor D6

Increased inflammation in mice deficient for the chemokine decoy receptor D6

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Multiple Roles for the C-terminal Tail of the Chemokine Scavenger D6

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