Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Chemokine Receptor CCR1

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_406


 CCR-1;  CD191;  CC-CKR-1;  CKR1;  CMKBR1;  HM145;  MIP1aR


Chemokines represent a large group of chemotactic proteins, with more than 50 members that regulate the trafficking and activation of immune cells. They mediate their activity by binding to cell surface chemokine receptors that belong to the G-protein coupled receptor (GPCR) superfamily. CCR1 is a chemokine receptor that responds to a large number of CC chemokines including CCL3 (MIP-1alpha), CCL5 (RANTES), CCL7 (MCP-3), CCL9 (MIP-1gamma), CCL15 (MIP1 delta), CCL23 (MIP-3), and with low affinity to CCL4 (MIP-1 beta) and CCL8 (MCP-2).

Structure and Functions

Human CCR1 is a serpentine protein comprising of 355 amino acids with three potential glycosylation sites and the characteristic seven membrane spanning architecture typical of GPCR’s (Fig. 1). The receptor has a consensus site for tyrosine sulfation, which affects the affinity and binding of some chemokine receptors to their ligand(s) and has been hypothesized to play an important role in regulating their activity (Liu et al. 2008). CCR1 has been cloned from a variety of species including, rhesus macaque, marmoset, pig, rabbit, dog, rat, and mouse. These protein sequences are highly homologous and the human receptor is 81% and 80% identical to the mouse and rat sequences, respectively (Fig. 2).
Chemokine Receptor CCR1, Fig. 1

Proposed membrane topography of CCR1. Membrane-spanning helices are defined on the basis of hydropathy analysis. Potential N-linked glycosylation sites are indicated by CHO and disulfide bonds by S-S

Chemokine Receptor CCR1, Fig. 2

Alignment of CCR1 sequences from human, rhesus macaque, marmoset, pig, rabbit, dog, rat, and mouse. Residues in white on a blue background reflect conserved amino acid residues. Residues in black on a white background reflect similar amino acid residues while residues of black on a cyan background reflect nonsimilar amino acids

CCRI plays an important role in host defense and is involved in regulating the chemotaxis of immune cells, a feature it shares in common with all other chemokine receptors. Dysregulation of this response leads to autoimmunity, and CCR1 has been associated with the pathophysiology of a number of diseases including rheumatoid arthritis, multiple sclerosis, transplant rejection, and allergic inflammation (Pease and Horuk 2012). CCR1 activates the Gi/o class of guanine nucleotide binding regulatory proteins (Murphy et al. 2000). This activation can, in turn, regulate several effectors, including adenylyl cyclase (inhibition), phospholipase C (activation), protein kinase C (activation), calcium flux (stimulation), and PLA2 (activation) (Nardelli et al. 1999).

Not all CCR1 ligands appear to mediate the same functions. For example although CCL3, CCL5, and CCL16 are all able to transduce signals through CCR1 in a human osteosarcoma line via Gi/Go, phospholipase C, and protein kinase Cdelta-mediated pathways, CCL16 can also signal via p38 MAP kinase and in contrast to the other two ligands does not induce calcium transients (Kim et al. 2005). The CCR1 ligands CCL3, CCL7, CCL5, and CCL15 can all inhibit adenylyl cyclase activity in cells transiently transfected with CCR1. Of these CCR1 ligands, however, only CCL15 was unable to signal via Ga14 or Ga16 coupled pathways (Tian et al. 2004). In addition, most of the CCR1 ligands are promiscuous and can activate other chemokine receptors (Murphy et al. 2000).

The cytomegalovirus, which causes acute, latent, and chronic infections in humans, has been shown to encode a CCR1 homolog, US28, which strongly activates classical G protein signal transduction networks within the cell (Gao et al. 1993; Neote et al. 1993). It can bind a number of chemokines including CCL3 and CCL5 with high affinity (Gao et al. 1993; Neote et al. 1993). In addition, US28 can signal in a ligand-independent, constitutive manner both through the Gq /phospholipase C pathway and through activation of the transcription factor NF-kappaB as well as through the cyclic AMP response element binding protein (Waldhoer et al. 2002).

CCR1-deficient mice generated by targeted gene disruption have revealed that CCR1 has a number of nonredundant functions in host defense and inflammation (Murphy et al. 2000). The role of CCR1 in host defense has been examined in a number of studies. When CCR1 knockout mice were challenged with Aspergillus fumigatus they showed an increase in mortality (Gao et al. 1997). Interestingly, knockout animals in the same study showed a 40% reduction, compared to their wild type littermates, in the size of lung granulomas induced by intravenous injection of Schistosoma mansoni eggs. In another study CCR1 knockout mice were challenged with the obligate intracellular protozoan parasite Toxoplasma gondii (Khan et al. 2001). In comparison with parental wild type mice, knockout mice showed an increased mortality to T. gondii in association with an increased tissue parasite load. The increased mortality appeared to be correlated to a reduction in the trafficking of neutrophils to inflamed areas in the knockout mice during early infection.

The role of CCR1 in host defense was examined in a model of viral-induced neurologic disease (Hickey et al. 2007). Intracerebral infection of mice with mouse hepatitis virus results in an acute encephalitis followed by a chronic demyelinating disease similar in pathology to that observed in multiple sclerosis. Although no increase in mortality was observed during the acute phase of disease following infection by 21 days postinfection, 74% of CCR1 knockout mice had died compared to only 32% mortality of wild type mice. The CCR1 knockout mice appeared to have a reduction in T-cell accumulation within the CNS during acute, but not chronic, disease. However, despite this other components of the immune response appeared to be unaltered in the knockout mice. Despite the reduction in T-cell trafficking into the CNS of CCR1 knockout mice during acute disease, components of host defense such as T-cell effector functions including cytolytic activity and proliferation and the expression of IFN-gamma remained unaltered. These findings suggest that T-cell and macrophage trafficking are not dependent on CCR1 and suggest a nonredundant role for CCR1 in promoting survival during chronic mouse hepatitis virus infection.

Both CCR1 and one of its ligands, CCL3, appear to be important for protection against infection with paramyxovirus pneumonia virus in mice (Domachowske et al. 2000). Infection of wild type mice with the virus results in pulmonary neutrophilia and eosinophilia accompanied by local production of CCL3. Mice deficient in CCL3 or its receptor CCR1 showed an attenuated inflammatory response to the virus with limited neutrophil trafficking and no eosinophils detected in bronchoalveolar lavage fluid. This was accompanied by a higher rate of mortality compared to wild type mice. These studies demonstrate that the CCL3/CCR1-mediated acute inflammatory response protects mice by delaying the lethal events of infection.

CCR1 also plays an important role in the pathopysiology of disease. In an animal model of inflammation CCR1 knockout mice were protected from pulmonary inflammation secondary to acute pancreatitis (Gerard et al. 1997). The protection from lung injury was associated with decreased levels of cytokines such as TNF-alpha suggesting that the activation of the CCR1 receptor is an early event in the systemic inflammatory response syndrome. CCR1 also appears to be involved in remodeling after myocardial infarction (Liehn et al. 2008). Studies with CCR1 deficient mice revealed that when myocardial infarction was induced, although initial infarct areas and areas at risk did not differ between groups, the infarct size increased in wild type mice compared to CCR1-deficient animals. This attenuation in infarct expansion was associated with preserved left ventricular function and was accompanied by an altered postinfarct inflammatory pattern characterized by diminished neutrophil infiltration, accelerated monocyte/lymphocyte infiltration, decreased apoptosis, increased cell proliferation, and earlier myofibroblast population in the infarcted tissue. This reduction in functional impairment and structural remodeling after myocardial infarction in CCR1 knockout animals suggests a role for this receptor in cardiac disease.

Since CCR1 appears to be expressed in demyelinating lesions in patients with multiple sclerosis (Trebst et al. 2001) and neutralization of one of its ligands, CCL3 is protective in a relapsing remitting model of multiple sclerosis in mice (Karpus et al. 1995). The role of the receptor was examined in a myelin oligodendrocyte glycoprotein (MOG)-induced model of disease in mice (Rottman et al. 2000). After immunization with MOG nearly all of the wild type animals developed disease with a clinical score of 2.5. In contrast, CCR1-deficient mice showed a decreased incidence to disease, less than 55%, and the severity of those with disease was reduced by around 50%.

While there is no question that CCR1 gene deletion studies in mice have been extremely useful in illuminating the role of this receptor both in normal and in pathophysiology, we need to exercise some caution in extrapolating these studies for human CCR1. It is known that the immune system in rodents can be very different from that in humans. For example, CCR1 is expressed constitutively in mouse neutrophils whereas it is inducible in human neutrophils (Murphy et al. 2000). Thus it is likely that the role of this receptor will be somewhat different in rodents than in humans when responding to an attack by pathogenic organisms. In addition, although CCR1 knockouts hint at a role for CCR1 in diseases like multiple sclerosis (Rottman et al. 2000) the fact that there is not a total abrogation of the disease in CCR1-deficient animals suggests that there is some redundancy in the system, and this might partly account for the failure of a number of CCR1 antagonists in clinical trials (J. E. Pease and Horuk 2009).

Regulation of Activity

In common with most GPCRs CCR1 undergoes receptor desensitization upon ligand binding (Neote et al. 1993). The mechanism involves phosphorylation of specific serines in the serine-rich carboxy-terminal tail (Richardson et al. 2000). The phosphorylation is mediated by G-protein receptor kinases (Vroon et al. 2004) and results in the uncoupling of the receptor from its G-protein and the recruitment of arrestin. These processes induce receptor internalization and terminate CCR1 signaling.

A series of CCR1 cytoplasmic tail mutants indicate that the phosphorylation sites for CCR1 are located in a cluster of serine and threonine residues between amino acids 340–346 (Richardson et al. 2000). Phosphorylation of these residues leads to receptor desensitization and inhibits CCL3 and CCL5-induced calcium transients and GTPase activity. Interestingly the activity of CCR1 can be independently regulated by unrelated chemokine receptors. For example, in a cell line coexpressing CCR1 and CXCR2, the CXCR2 ligand CXCL8 was able to cross-phosphorylate CCR1 and desensitize its ability to stimulate GTPase activity and Ca2+ mobilization. Conversely CCR1 ligands were able to induce the phosphorylation and desensitization of CXCR2.

Retinoic acid has been shown to increase the expression of CCR1 in human monocytes (Ko et al. 2007). It increased calcium influx and chemotactic activity in response to the CCR1 ligands CCL15, CCL3, and CCL5 and appears to be mediated through a p38 MAPK and ERK pathway since pretreatment with inhibitors of these kinases blocked the retinoic acid-induced effects.

In an animal model of myocarditis a CCR1 antagonist, BX 471, was able to inhibit disease and improve cardiac function (Futamatsu et al. 2006). The beneficial effects of the antagonist were likely associated with its ability to block T cell proliferation and suppress ERK1/2 and JNK activities in T cells stimulated with myosin.

Pharmacological Activities

A variety of CCR1 antagonists have been described in the literature and have been recently reviewed (Pease and Horuk 2009). Of this large number of antagonists seven have progressed into the clinic and only one is still currently active (Table 1 and Fig. 3). The first clinical CCR1 antagonist described was a diacyl piperazine BX 471 from Berlex (1, Fig. 3) that was more than 1000-fold selective for CCR1 (Pease and Horuk 2009). The antagonist was a potent CCR1 blocker with a KD of 1.0 nM for human CCR1; however, it was poorly cross-reactive with rat, and mouse, CCR1 (KD 121, and 200 nM, respectively). The antagonist was efficacious in a variety of animal models including a rat model of multiple sclerosis (Horuk 2009). Although the safety profile of BX 471 was excellent, its development was stopped after the clinical phase II study failed to show a reduction in the number of new inflammatory CNS lesions (Horuk 2009).
Chemokine Receptor CCR1, Table 1

Summary of clinical development of CCR1




Affinity (nM)


Clinical Phase



Schering AG (Berlex)

BX 471


MS, Psoriasis Endometriosis


No efficacy



MLN 3701




No longer reported



MLN 3897




No efficacy in RA







No efficacy







No efficacy














No efficacy in RA

Abbreviations: BMS, Bristol-Myers Squibb; GSK, GlaxoSmithKline; MM, multiple myeloma; MS, multiple sclerosis; RA, rheumatoid arthritis

Chemokine Receptor CCR1, Fig. 3

Structures of CCR1 antagonists that have entered clinical trials. Data shown represents inhibition of receptor binding, Ki , unless otherwise stated

Millennium has disclosed MLN3897 (2, Fig. 3) (Carson et al. 2004), a substituted pyridylbenzoxepine, with high affinity binding for CCR1 (Ki 2.3 nM). MLN3897 was effective in vivo and demonstrated an EC50 of 0.03 mg/kg in inhibiting CCL3-induced immune cell recruitment in a guinea pig skin sensitization model (Pharmacokinetic studies revealed that it had a half-life of 3 h in rat and oral bioavailability of 35% in rat and 100% in dog). The compound entered clinical trials for rheumatoid arthritis, but development was terminated because it had failed to reach its clinical endpoint in a phase II trial (Vergunst et al. 2009).

Pfizer disclosed CP-481715 a quinoxaline-2-carboxylic acid derivative (3, Fig. 3) (Gladue et al. 2010). This inhibitor is a competitive and reversible antagonist and is more than 100-fold selective for CCR1 as compared to a panel of G-protein coupled receptors (Gladue et al. 2010). Unfortunately, CP-481715 was species specific for human CCR1 precluding its evaluation in classical animal models of disease. To circumvent this problem, Pfizer researchers generated transgenic mice expressing human CCR1 and demonstrated efficacy in models of inflammation in these animals (Gladue et al. 2006). CP-481715 successfully completed phase I safety studies and demonstrated efficacy in a 16 patient phase Ib clinical trial (Gladue et al. 2010). Based on these data CP-481715 entered phase II studies, but the trial was stopped after 6 weeks because the compound did not demonstrate any efficacy (Gladue et al. 2010).

Chemocentryx has disclosed a number of CCR1 inhibitors and their lead compound, CCX354, (Tables 1 and 4, Fig. 3) is currently in phase II clinical trials (Dairaghi et al. 2011). The antagonist is a potent inhibitor with a Ki of 1.5 nM. In addition, CCX354 also blocked the chemotaxis of THP-1 cells that were induced with synovial fluid from rheumatoid arthritis patients. The antagonist was specific for CCR1 and had no effect on the induction of chemotaxis through 13 other chemokine receptors at concentrations of up to 10 uM. Based on favorable animal studies compound CCX354 entered clinical trials for rheumatoid arthritis. Phase II clinical trial data for CCX354 reported at the recent American College of Rheumatology meetings showed that at a once daily dose of 200 mg the antagonist was safe and well tolerated by patients with rheumatoid arthritis. Furthermore the compound reached its clinical end points in the study (reduction in disease score and in the levels of proinflammatory markers) (Tak et al. 2012).

Astra Zeneca identified CCR1 antagonists from its screening of an in house library and optimization yielded the clinical candidate AZD4818 a spirocyclic piperidine derivative (5, Fig. 3) (Kerstjens et al. 2010). The drug inhibited CCL3 binding to human mouse and rat CCR1 receptors (no affinity reported) and blocked chemotaxis of human monocytes (Kerstjens et al. 2010). Based on these and other nonreported data the CCR1 antagonist entered clinical trials for the treatment of chronic obstructive pulmonary disease (COPD) (Kerstjens et al. 2010). The CCR1 antagonist was given by inhalation at a dose of 300 ug twice daily for 4 weeks to patients with COPD. Although the drug was well tolerated it failed to meet its clinical end points, and development was terminated (Kerstjens et al. 2010).

BMS have been interested in developing CCR1 antagonists for treating rheumatoid arthritis (Merritt and Gilchrist 2012) and recently described their efforts in identifying potent CCR1 inhibitors (Cavallaro et al. 2012; Gardner et al. 2013). The preclinical candidate identified from these studies BMS-457 had excellent potency (Ki 0.8 nM) and was specific for CCR1 but exhibited significant QT prolongation in both rabbits and dogs during advanced safety studies, thus, further development of the antagonist was halted (Gardner et al. 2013). Despite these setbacks the company reported that it had identified a clinical candidate BMS-817399 (Tables 1 and 6 Fig. 3) (Santella et al. 2014) that had none of the safety issues of BMS-457. Unfortunately recent clinical phase II studies reported by the same group indicated that although BMS-817399 was safe and well tolerated it showed no evidence of clinical efficacy in RA patients with moderate to severe disease activity (Kivitz et al. 2014). The trial did not fail because of a lack of efficacy of BMS-817399, because the levels of the compound were at least 17-fold above the IC90 for the CCR1 ligand CCL3 (Kivitz et al. 2014) suggesting that CCR1 is not a clinically relevant target for patients with moderate to severe RA.

In addition to these clinical programs a large number of nonclinical CCR1 antagonists have been described in both the published and in the patent literature, and since these have been extensively reviewed in a number of publications the reader is directed to these for an overall summary of ongoing progress in the CCR1 field (Pease and Horuk 2009; Zhang et al. 2013).

Clinical Use

No CCR1 compounds have been clinically approved.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of PharmacologyUC DavisDavisUSA