Opposite Fate of Endocytosed CCR7 and Its Ligands: Recycling versus Degradation

Otero, Carolina; Groettrup, Marcus; Legler, Daniel F.

doi:10.4049/jimmunol.177.4.2314

Cited by 116 publications

(189 citation statements)

References 63 publications

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“…Over time, the synergistic activities will be overcome by a persistent production of inflammatory chemokines that will lead to high concentrations of CCL2 and CCL7, rendering CCR2 activity independent from non-ligand chemokines. A recent report on the fate of CCR7 and its ligands CCL19 and CCL21 showed different destinies for the receptor and the agonist [38]. Internalization and re-expression experiments indicated that reexpressed CCR7 is fully active and can mediate chemotaxis.…”

Section: Discussionmentioning

confidence: 97%

“…Depending on the chemokine receptor, different intracellular destinies have been proposed after agonist-induced internalization [36][37][38]. The data we have obtained on CCR2 internalization prompted us to investigate the re-expression rate of the receptor after CCL7-or CCL7 plus CCL21-induced stimulation (Fig.…”

Section: Re-expressed Ccr2 Is Fully Functional and Can Mediate Cellulmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 97%

Section: Re-expressed Ccr2 Is Fully Functional and Can Mediate Cellulmentioning

confidence: 99%

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Kuscher¹,

Danelon²,

Paoletti³

et al. 2009

Eur J Immunol

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“…Both ligands have similar affinity to CCR7 (4,5), but drive different fates: CCL19 signaling leads to receptor internalization and temporal desensitization while CCL21 can signal from the cell membrane (6,9,40,44,45), a well described liganddependent process for G-protein-coupled receptors. This differential fate of activated CCR7 could lead to increased receptor density and signaling on the cell side dominated by CCL21 (46), consistent with our observation of increased DC response to CCL21 gradients above 50 nM (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19

Haessler

Pisano

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

186

184

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Dendritic cell (DC) homing to the lymphatics and positioning within the lymph node is important for adaptive immunity, and is regulated by gradients of CCL19 and CCL21, ligands for CCR7. Despite the importance of DC chemotaxis, it is not well understood how DCs interpret gradients of these chemokines in a complex 3D microenvironment. Here, we use a microfluidic device that allows rapid establishment of stable gradients in 3D matrices to show that DC chemotaxis in 3D can respond to CCR7 ligand gradients as small as 0.4%, which helps explain how DCs sense lymphatic vessels in an environment where broadcast distance for chemokine diffusion is hindered by convective flows into the vessel. Interestingly, DCs displayed similar sensitivities to both chemokines at small gradients (≤60 nM∕mm), but migrated more efficiently towards higher gradients of CCL21, which unlike CCL19 binds strongly to matrix proteoglycans and signals without the need for internalization. Furthermore, cells preferentially migrated towards CCL21 when exposed to equal and opposite gradients of CCL21 and CCL19 simultaneously, even when matrix-binding of CCL21 was prevented. Although these ligands have similar binding affinity to CCR7, our results demonstrate that, in a 3D environment, CCL21 is a more potent directional cue for DC migration than CCL19. These findings provide new quantitative insight into DC chemotaxis in a physiological 3D environment and suggest how CCL19 and CCL21 may signal differently to fine-tune DC homing and positioning within the lymphatic system. These results also have broad relevance to other systems of cell chemotaxis, which remain poorly understood in the 3D context.D endritic cells (DCs) are considered the most potent and professional antigen-presenting cells. DCs are positioned throughout the periphery, and when activated, migrate to lymphatic vessels and into lymph nodes, where they can direct antigen-specific Tcell responses. Upon activation or maturation, DCs upregulate the C-C chemokine-receptor CCR7, which allows them to sense and home towards CCR7 ligand-secreting lymphatic vessels and lymph nodes (1). The two known ligands for CCR7 are the C-C chemokines CCL21 and CCL19 (2); both are secreted by stromal cells in the lymph node paracortex to properly position DCs with CCR7 þ naïve T cells for their activation. CCL21, but not CCL19, is also expressed by the endothelium of lymphatic vessels in the periphery (1). Thus, CCR7-mediated chemotaxis is critical for DC homing to, and positioning within, lymph nodes and for T cell activation there (3).CCL19 and CCL21 function as directional signals presumably by virtue of concentration gradients (∇C) that guide DCs towards areas of increasing concentrations. Interestingly, CCL19 and CCL21 have similar binding affinities for CCR7 (4-6) and similar chemotactic potential for DCs and T cells under 2D conditions (7,8), but differ in their internalization (8, 9) as well as their binding affinity to extracellular matrix (ECM) proteoglycans. Specifically, the positively charged C t...

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“…The chemokine receptor CCR7, for instance, follows the clathrin-dependent pathway involving dynamin, Eps15, Rab5 and early endosomal antigen-1 (EEA1) [19,20]. After internalization, CCR7 enters the recycling compartment and traffics back to the plasma membrane to actively participate in directed cell migration, whereas its ligand CCL19 is sorted to lysosomes for degradation [19].…”

Section: Keeping Chemotactic Receptors In Placementioning

confidence: 99%

“…After internalization, CCR7 enters the recycling compartment and traffics back to the plasma membrane to actively participate in directed cell migration, whereas its ligand CCL19 is sorted to lysosomes for degradation [19]. Interestingly, ubiquitylation of CCR7 serves as control mechanism for receptor trafficking as an ubiquitylationdeficient mutant on one hand reduces the intracellular pool of CCR7 in the steady-state and, on the other hand, shows a significant retardation in receptor recycling after ligandmediated endocytosis, resulting in a reduced CCR7 surface pool and in inefficient cell migration [21].…”

Section: Keeping Chemotactic Receptors In Placementioning

confidence: 99%

On the move: endocytic trafficking in cell migration

Maritzen

Schachtner

Legler

2015

Cell. Mol. Life Sci.

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Directed cell migration is a fundamental process underlying diverse physiological and pathophysiological phenomena ranging from wound healing and induction of immune responses to cancer metastasis. Recent advances reveal that endocytic trafficking contributes to cell migration in multiple ways. (1) At the level of chemokines and chemokine receptors: internalization of chemokines by scavenger receptors is essential for shaping chemotactic gradients in tissue, whereas endocytosis of chemokine receptors and their subsequent recycling is key for maintaining a high responsiveness of migrating cells. (2) At the level of integrin trafficking and focal adhesion dynamics: endosomal pathways do not only modulate adhesion by delivering integrins to their site of action, but also by supplying factors for focal adhesion disassembly. (3) At the level of extracellular matrix reorganization: endosomal transport contributes to tumor cell migration not only by targeting integrins to invadosomes but also by delivering membrane type 1 matrix metalloprotease to the leading edge facilitating proteolysis-dependent chemotaxis. Consequently, numerous endocytic and endosomal factors have been shown to modulate cell migration. In fact key modulators of endocytic trafficking turn out to be also key regulators of cell migration. This review will highlight the recent progress in unraveling the contribution of cellular trafficking pathways to cell migration.

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Opposite Fate of Endocytosed CCR7 and Its Ligands: Recycling versus Degradation

Cited by 116 publications

References 63 publications

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19

On the move: endocytic trafficking in cell migration

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