Tuning inflammation and immunity by chemokine sequestration: decoys and more

Mantovani, Alberto; Bonecchi, Raffaella; Locati, Massimo

doi:10.1038/nri1964

Cited by 435 publications

(378 citation statements)

References 106 publications

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“…Cxcr7 function is important for heart development (Sierro et al, 2007), interneuron migration (Sánchez-Alcañiz et al, 2011;Wang et al, 2011), leukocyte trafficking (Cruz-Orengo et al, 2011) and for promoting breast and lung tumorigenesis (Miao et al, 2007;Luker et al, 2012). Some of these in vivo studies, as well as those conducted in vitro (Luker et al, 2010;Naumann et al, 2010), are consistent with the idea that Cxcr7 serves as a receptor that effectively scavenges Cxcl12a and does not influence downstream signaling pathways (reviewed by Mantovani et al, 2006). Despite its importance in controlling Cxcl12 activity in the tissue, the molecular mechanisms promoting the decoy function of Cxcr7 are unknown.…”

Section: Introductionsupporting

confidence: 63%

“…We monitored the subcellular localization of Cxcr7b-ECFP fusion protein relative to that of mCherry fused to Rab5, which labels early and recycling endosomes (Gorvel et al, 1991), Rab11, which is found in recycling endosomes (Ullrich et al, 1996), or Rab7, a late endosomal marker (Gorvel et al, 1991;Méresse et al, 1995), or relative to Lamp1-DsRedmonomer fusion protein, which is localized to late endosomes and lysosomes (Rohrer et al, 1996). Consistent with its suggested role as a molecular sink recycling between the membrane and intracellular compartments (Weber et al, 2004;Mantovani et al, 2006), we could identify Cxcr7b in Rab5-positive vesicles at stages when PGCs migrate (Fig. 1I).…”

Section: -Arrestins Control the Endosomal Sorting Of Cxcr7bmentioning

confidence: 94%

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β-arrestin control of late endosomal sorting facilitates decoy receptor function and chemokine gradient formation

Mahabaleshwar

Tarbashevich

Nowak³

et al. 2012

Development

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SUMMARYA crucial regulator of Cxcl12 is the decoy receptor Cxcr7, which controls the level of the chemokine in the tissue. The molecular mechanisms that enable Cxcr7 to function as an efficient molecular sink are not known. Using zebrafish primordial germ cells as a model, we identify a novel role for -arrestins in controlling the intracellular trafficking of Cxcr7. -arrestins facilitate the recycling of Cxcr7 from late endosomal compartments back to the plasma membrane, whereas the internalized ligand undergoes lysosomal degradation. -arrestins thus function in regulating chemokine gradient formation, allowing responding cells to discriminate between alternative migration targets in vivo.

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Section: Introductionsupporting

confidence: 63%

Section: -Arrestins Control the Endosomal Sorting Of Cxcr7bmentioning

confidence: 94%

β-arrestin control of late endosomal sorting facilitates decoy receptor function and chemokine gradient formation

Mahabaleshwar

Tarbashevich

Nowak³

et al. 2012

Development

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“…Dampening of inflammatory responses by chemokines is controlled by several mechanisms including enzyme cleavage [25] or degradation by decoy receptors [33]. The decoy receptor D6 can bind and scavenge many CC inflammatory chemokines [34,35] such as CCL2 and CCL7.…”

mentioning

confidence: 99%

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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“…This restores tissue homeostasis and prevents the persistent inflammation that lies at the heart of many destructive immunopathologies and promotes tumor formation (3). Resolution is aided by D6, a 7TMR related to CCR1-5, which binds 12 of the chemokine ligands for these receptors (4,5) and is expressed, at least in humans, by lymphatic endothelial cells, trophoblasts, and some leukocyte populations (6,7). D6 null mice show prolonged exaggerated responses to cutaneous inflammatory stimuli and tumor induction (8 -10), enhanced leukocyte infiltration during allergic lung inflammation (11), and increased sensitivity to experimentally induced fetal resorption (7).…”

mentioning

confidence: 99%

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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Tuning inflammation and immunity by chemokine sequestration: decoys and more

Cited by 435 publications

References 106 publications

β-arrestin control of late endosomal sorting facilitates decoy receptor function and chemokine gradient formation

β-arrestin control of late endosomal sorting facilitates decoy receptor function and chemokine gradient formation

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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