Every process in the body is regulated by a complex network of interactions between different molecules and cells. Chemokines, for example, are tiny molecules produced by a cell that are involved in a range of processes, from development to immune responses and cancer.

When chemokines bind to a specific protein on another cell, called the chemokine receptor, it stimulates different signaling pathways inside the cell. Consequently, chemokine receptors are equally important for regulating processes as diverse as the movement of cells during development and growth, or activating immune responses.

Mammals have over 20 different chemokine receptors, and the same receptor can have different roles depending in which cell type it is found in. For example, in one cell type it may stimulate an action such as cell growth, but in another, it may block this process. Until now, it was unclear how chemokine receptors can achieve such different effects. One theory was that chemokine receptors initiate a distinct signaling cascade, a phenomenon termed ‘signaling bias’, depending on the type of chemokine or receptor.

Here, Malhotra et al. used zebrafish embryos to investigate how four specific chemokine receptors regulate different events during early development. They found that the same chemokine receptor could direct different reactions in distinct cell types, while different receptors could also cause the same response in a specific cell type. In other words, the effect of a chemokine receptor depends on the cell type rather than the type of receptor.

Since each of these receptors was able to control processes that it normally does not regulate in other cells, Malhotra et al. suggest that different chemokine receptors provide the same generic signal when activated, which the specific cell types then interpret accordingly.

A next step will be to test how other chemokine receptors behave in different contexts, for example during an immune response. If the receptors work on the same principle regardless of the process, it could help to explain why faulty expression of chemokine receptors play such an important role during development and in disease. It could further highlight why blocking one receptor may not have any consequences, as they are dispensable and can be replaced by other receptors in the cell.

Chemokines are small proteins that signal upon binding seven-pass-transmembrane G protein-coupled receptors (GPCRs) (Zlotnik and Yoshie, 2000). Chemokine receptors are classified into four categories namely, CXCR, CCR, XCR and CX3CR (Nomiyama et al., 2011). Chemokines were originally shown to function in the context of immune response, but were thereafter implicated in a range of developmental processes such as angiogenesis (Strieter et al., 1995), neural development (Zou et al., 1998) and migration of non-immune cells. Following binding to their ligands, chemokine receptors activate a wide range of effectors, including adenylyl cyclases, phospholipase isoforms, protein tyrosine kinases, ion channels, and mitogen-activated protein kinases (MAPKs). These responses can result from the activation of G proteins, as well as from other second messengers to initiate G-protein-independent signaling (Steen et al., 2014). For example, in addition to signaling through the G protein Gαi and Gβγ, chemokine receptors can initiate JAK/STAT signaling and signal through β-arrestin, in the context of chemotaxis of hematopoietic progenitor cells and in the context of activation and release of granules in neutrophils, respectively (Barlic et al., 2000; Zhang et al., 2001). Thus, chemokine receptor signaling through a range of second messenger molecules potentially expands an individual chemokine receptor’s ability to control qualitatively different cellular responses.

In many cases, the same chemokine receptor is expressed in different cell types, where it initiates very different types of biological responses. For example, Cxcr4 expression in hematopoietic progenitors is important for these cells’ mobilization (Möhle et al., 1998), yet, the same receptor, when expressed in neuronal progenitor cells inhibits their proliferation (Krathwohl and Kaiser, 2004). Similarly, CCR7 is expressed by T lymphocytes to facilitate their homing to secondary lymphoid organs (Sallusto et al., 1999), but it is also expressed in and important for the development of the human placenta (Drake et al., 2004). On the other hand, in early zebrafish embryos Ccr7 is expressed broadly and is involved in proper dorsoventral axis formation (Wu et al., 2012). These observations raise the question of how different chemokine receptors control such a wide range of different processes.

Several models have been suggested to explain this phenomenon and these are collectively referred to as ‘signaling bias’ (Steen et al., 2014). Related to that, it has been recently demonstrated that the extracellular and membrane-spanning domains of chemokine receptors are not responsible for signaling specificity (Xu et al., 2014). In this work, the extracellular and transmembrane domains of rhodopsin were combined with the intracellular domains of Cxcr4. In this case, in response to light (the ligand of rhodopsin), the chimeric protein elicited Cxcr4 signaling, such that it could direct the migration of T-cells. A receptor could show signaling bias by preferentially activating different signaling cascades depending on the specific ligand or agonist it binds. For example, when chemokine receptor Ccr7 is bound by Ccl19, it induces β-arrestin recruitment more potently than when it is bound by Ccl21 (Kohout et al., 2004). Another type of signaling bias, which could increase the range of processes that chemokine receptors control involves the initiation of different signaling cascades upon binding of the same ligand. For example, Cxcr4 interaction with its ligand Cxcl12 triggers both Gαi and β-arrestin signaling (Dumstrei et al., 2004; Sun et al., 2002; Thomsen et al., 2016), while Cxcr7 receptor interaction with Cxcl12 was reported to activate β-arrestin but not G-protein signaling (Rajagopal et al., 2010). Overall, the above-mentioned studies help explain how chemokine receptor signaling bias occurs, as these receptors and their ligands can differentially activate certain second messengers. However, previous studies have not thoroughly examined the relevance of specific differences in second messenger activation with respect to the resulting biological responses in vivo.

Here, we demonstrate that distinct responses to chemokine receptor signaling depend on the responding cell type rather than on the specific receptor activated by its ligand. We demonstrate this principle via chemokine receptor signaling in zebrafish embryos by examining the function of four different chemokine receptors: Cxcr4a, Cxcr4b, Ccr7, and Ccr9. We gathered several lines of evidence to show that these chemokine receptors initiate specific biological processes in a way that depends on the cell types they are expressed in. These results present chemokine receptor signal interpretation module (CRIM) as a new mechanism for biasing the biological response resulting from chemokine receptor signaling. Specifically, we showed that each of those receptors is capable of controlling biological processes that it normally does not regulate, indicating that different chemokine receptors provide the same signal when activated. We thus suggest that different cell types express specific response modules or CRIM that interpret generic signals produced by different types of chemokine receptors.

In this work, we show that the same chemokine receptor can direct distinct responses in different cell types, while different receptors elicit the same biological response in a specific type of cells. These findings are consistent with the idea, that the biological consequences of chemokine receptor signaling depend on the cell type rather than on qualitative differences in the signal produced by specific receptors. We demonstrate that the identity of the activated receptor is immaterial for the actual interpretation of the signal that results in distinct biological responses in different cells. Our findings suggest that based upon their specific differentiation state, different cell types contain specific chemokine receptor signal interpretation modules (CRIM) that interpret the generic signals produced by chemokine receptors. The suggestion that the same receptor can elicit different cellular responses is presented graphically in Figure 8A. While it is possible that different receptors induce the response more efficiently or less, the qualitative features of the signaling, at least for the receptors and processes we examined, appear to be generic. Consistently, the cell-specific biological response to the signal appears to be robust as it can be observed when different levels of the receptor were expressed in the cells (Figure 3—figure supplement 1). This situation is analogous to heterozygosity for mutated chemokine and chemokine receptor alleles that has no phenotypic consequences (Knaut et al., 2003; Kupperman et al., 2000), as well as to a situation where the level of the Cxcr4b and Cxcl12a is altered by alleviating the miRNA regulation, a manipulation that has no phenotypic consequences (Goudarzi et al., 2013).

Figure 8 with 1 supplement see all

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In support of our model, it was shown that in the context of the immune system the same cell type can respond in a similar way to signaling of different chemokine receptors. For example, CCR1, CXCR1 and CXCR2 were shown to trigger arrest of rolling monocytes (Ley, 2003; Luscinskas et al., 2000; Weber et al., 2001). An interesting feature of the model we propose is that it allows positioning of cells by different ligands expressed in spatially distinct locations. Such a scenario was described in the case of neutrophil mobilization from the bone marrow to the blood stream and is schematically presented in Figure 8—figure supplement 1A. In this case, the positioning of the cells is dictated by a tug-of-war situation in which CXCL12 expressed by osteoblasts functions as a retention signal that maintains the neutrophils within the bone and CXCL2 emanating from the endothelium that attracts the cells toward the blood vessels (Eash et al., 2010). Another aspect of the model is presented schematically in Figure 8B. In this case, concurrent trafficking of different cell types to distinct locations can be achieved using different chemokines. For example, in humans two subsets of memory T-cells, central memory T cells (T_CM, CCR7⁺) and effector memory T-cells (T_EM, CCR7^–) exhibit different behavior and localization. T_CM tend to home to secondary lymphoid organs, where ligand for CCR7 is expressed, whereas TEM, that express CCR1, CCR3, CCR5 migrate toward the inflamed tissue, where the corresponding ligands for those receptors are expressed (Sallusto et al., 1999). Thus, while several cell types share CRIMs, their actions are compartmentalized by dynamic and distinct spatiotemporal expression patterns of the receptors and their cognate ligands.

In the context of embryonic development, the differentiation of cells and tissues dictates the presence of specific downstream signaling molecules in different cell types, which facilitates differential interpretation of a generic signal generated by chemokine receptors. This differential cell competence allows concomitant processes to be controlled by chemokines by regulating the expression pattern of receptors and ligands in specific cell populations. For example, during zebrafish gastrulation Cxcr4a regulates endodermal cell movement by controlling adhesion levels in response to uniform chemokine signaling. At the same time, the migration of germ cells is directed by specific patterns of a different ligand that interact with the chemokine receptor Cxcr4b. These two different events can take place at the same time within the same region of the embryo despite the generic signal the receptors produce as the different cell types interpret it differently.

A particular feature of the generic downstream signaling is to increase the robustness of physiologically important processes through cooperation between different receptors in supporting specific processes. For example, by inhibiting the function of lipid-activated GPCRs, we revealed a novel function of Cxcr4 in promoting epiboly during gastrulation. This function was not described before, as Cxcr4 function is redundant to that of the LPA and S1P receptors. Similarly, T cells utilize Ccr9, Cxcr4 and Ccr7 for homing to the thymus in early mouse embryos, but eliminating the function of one or two of these receptors is not sufficient to abrogate thymus homing. Only in the absence of all three receptors is thymic homing of T-cells completely abolished (Calderón and Boehm, 2011). The implication of these findings is that to determine the role of chemokine signaling in a certain process, one should mutate all the chemokine receptors/GPCRs in a tissue. Our findings suggest that even if cells express multiple chemokine receptors, at a specific differentiation or physiological state they can respond to receptor activation in only one way, such as directed migration (Doitsidou et al., 2002), interaction with other cell types (Nair and Schilling, 2008) or embryonic patterning (Wu et al., 2012). As S1P/LPA receptors and Cxcr4b were able to elicit a similar biological response (Figure 6), this principle could be relevant for other G-protein-coupled receptors. Indeed, G-protein-coupled receptors of different families were shown to result in similar responses in other contexts. For example, neutrophils were shown to migrate towards fMLP and Cxcl8, ligands that bind distinct receptors (Gallin et al., 1983; Ludwig et al., 1997). Interestingly, despite the fact that the receptors for these ligands (fMLP receptor and Cxcr2, respectively) differ in some different downstream effectors they activate, the response to ligand binding is qualitatively identical (Heit et al., 2008). Thus, despite differences in the biochemical response to such signals, the specific biological response of a specific cell type is identical.

In light of our findings, chemokine-mediated attraction, fugetaxis or retrotaxis do not represent the activation of distinct signaling pathways. We suggest that reverse migration does not involve a qualitatively different signaling pathway, but represents a lack of receptor signaling due to internalization and desensitization processes, as proposed by Holmes and colleagues based on mathematical modeling (Holmes et al., 2012). In contrast, cells that encounter regions where lower levels of the ligand are expressed maintain the receptor on their membranes and are therefore retained within those regions by positively responding to the chemokine distribution in the tissue. It would be interesting to determine if in other cases where retrotaxis was described for example in the case of LXA4 (Hamza et al., 2014), which has also been shown to act as a potent chemoattractant (Maddox and Serhan, 1996), G-protein-coupled receptor internalization or desensitization of signaling provides the basis for reverse migration.

While we present here a role for a chemokine receptor signal interpretation modules (CRIM) in a range of biological process in the context of different receptors function, some previous findings report on qualitatively different responses in the same cell type (Gerszten et al., 1999). Such cases do not necessarily contradict our model if the cells investigated undergo a maturation process, which alter their interpretation of the signal. We suggest that since, among other differences, specific cell types differ from one another by the specific response network they harbor, the outcome of chemokine signaling can differ between cells of different lineages and sublineages (see Figure 8—figure supplement 1B for a graphical explanation of the concept). Apparently differential response to chemokine signaling was demonstrated in the case of leukocyte arrest in response to CXCL1 activation of CXCR2, while CCL2 binding to CCR2 could not lead to a similar biological response in the same cell type (Huo et al., 2001). These findings are, however, contradictory to another study according to which CCL2 could actually induce leukocyte arrest (Gerszten et al., 1999). It would thus be interesting to critically examine such contrasting results in light of the model we suggest. Similar statements suggesting different biological responses elicited by the action of distinct ligands (e.g. [Zohar et al., 2014]) should be carefully assessed for equal experimental starting conditions and cell states between the different treatments.

While the principle of generic signals and cell-specific interpretation presented here was tested in the context of chemokine receptors, it could also be relevant for other receptor families such as receptor tyrosine kinases. For example, for the receptor tyrosine kinase EGFR, the same ligand was shown to control different biological processes upon activating a specific receptor within different cell types (Freeman and Gurdon, 2002; Queenan et al., 1999). Similarly, activation of the G-protein-coupled receptor for Acetylcholine was shown to induce different biological responses in different cell types (Caulfield, 1993). Such findings were interpreted as an indication that the same signaling pathway can lead to multiple cellular and developmental consequences, depending on the context and time (Freeman and Gurdon, 2002).

While based on our results chemokine receptors elicit qualitatively similar signals, which appear to be equivalent to those LPA and S1P receptors produce, the signal may not be universal for all GPCRs. Indeed, the endoderm migration defect resulting from loss of Apela, a GPCR ligand (Pauli et al., 2014) could not be suppressed by expression of Cxcr4b or CCR9 with their corresponding ligands (data not shown). Further experiments should be conducted to determine if this finding reflects a qualitative difference between the signal the chemokine receptors produce and the receptor for Apela. Alternatively, the dynamics of the expression of Apela and its receptor, which we could not mimic by uniformly expressing receptors and their ligands is responsible for this result.

Our findings suggest that in addition to the expression of classic cell-specific differentiation markers, an important aspect of cell specification that dictates its fate and behavior is the expression of signaling interpretation modules. While the specific components of these modules are likely to be expressed in many cell types, the relative level of second messenger molecules as well as of molecules further downstream could provide specificity to the response. Understanding this relatively less explored yet important layer of cell differentiation is likely to shed more light on how cells regulate a range of processes and respond to different signals.

We suggest that based on the differentiation state of a cell, these second messengers and molecules further downstream of them could be present in different proportions. In this way, the interpretation of GPCR signaling would vary in each cell type, leading to different outcomes. It would thus be interesting to determine those parameters for different responses to chemokine receptors and determine if one can modulate the consequence of chemokine signaling in a predicted way.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Divyanshu Malhotra

   Institute for Cell Biology, ZMBE, Muenster, Germany

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0838-2387

2. Jimann Shin

   Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri

   Contribution

   Resources, Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1027-0517

3. Lilianna Solnica-Krezel

   Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri

   Contribution

   Resources, Supervision, Funding acquisition, Methodology, Project administration, Writing—review and editing

   Competing interests

   Reviewing editor, eLife

4. Erez Raz

   Institute for Cell Biology, ZMBE, Muenster, Germany

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   erez.raz@uni-muenster.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6347-3302

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