The CC chemokine antagonist Met‐RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3

Elsner, Jörn; Petering, Holger; Höchstetter, Renate; Kimmig, Daniela; Wells, Timothy N.C.; Kapp, Alexander; Proudfoot, Amanda

doi:10.1002/eji.1830271122

Cited by 121 publications

(72 citation statements)

References 67 publications

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“…The recruitment of eosinophils to the caecum was partly preserved (Fig. 3), suggesting a secondary specificity for another chemokine-mediated recruitment step, e.g., CCR1, which is expressed and active in eosinophils (46,47). Eosinophils were found in regional, but not distant, lymph nodes of CCR3 Ϫ/Ϫ animals (Fig.…”

Section: Discussionmentioning

confidence: 96%

CCR3 Is Required for Tissue Eosinophilia and Larval Cytotoxicity After Infection withTrichinella spiralis

Gurish

Humbles

Hong

et al. 2002

The Journal of Immunology

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The CCR3 binds at least seven different CC chemokines and is expressed on eosinophils, mast cells (MC), and a subset of Th cells (Th2) that generate cytokines implicated in mucosal immune responses. Using mice with a targeted disruption of CCR3 (CCR3−/−) and their +/+ littermates, we investigated the role of CCR3 in the amplification of tissue eosinophilia and MC hyperplasia in the mouse after infection with Trichinella spiralis. In CCR3−/− mice, eosinophils are not recruited to the jejunal mucosa after infection and are not present in the skeletal muscle adjacent to encysting larvae. In addition, the number of cysts in the skeletal muscle is increased and the frequency of encysted larvae exhibiting necrosis is reduced. The CCR3−/− mice exhibit the expected MC hyperplasia in the jejunum and caecum and reject the adult worms from the small intestine at a normal rate. This study is consistent with distinct functions for MC (adult worm expulsion) and eosinophils (toxicity to larvae) in immunity to a helminth, T. spiralis, and defines the essential requirement for CCR3 in eosinophil, but not MC recruitment to tissues.

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Section: Discussionmentioning

confidence: 96%

CCR3 Is Required for Tissue Eosinophilia and Larval Cytotoxicity After Infection withTrichinella spiralis

Gurish

Humbles

Hong

et al. 2002

The Journal of Immunology

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“…While chemokines are thought to primarily regulate the migration pattern of eosinophils, they have also been shown to promote eosinophil activation and function (Zimmermann et al, 2003). For example, RANTES and eotaxin-1 have been shown to promote cellular activation and modulate the respiratory burst (Elsner et al, 1997(Elsner et al, , 1999. Data presented eosinophil peroxidase release (A) and eosinophil-derived neurotoxin (EDN) plasma levels (B) from control subjects (n < 31), sickle cell anaemia patients (SCA, n < 27) and sickle cell anaemia patients on hydroxycarbamide therapy (SCAHC, n < 28).…”

Section: Discussionmentioning

confidence: 99%

Hydroxycarbamide reduces eosinophil adhesion and degranulation in sickle cell anaemia patients

et al. 2013

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SummaryInflammation, leucocyte and red cell adhesion to the endothelium contribute to the pathogenesis of sickle cell anaemia. Neutrophils appear to be important for vaso-occlusion, however, eosinophils may also participate in this phenomenon. The role of eosinophils in the pathophysiology of sickle cell anaemia (SCA) and the effect of hydroxycarbamide (HC) therapy on the functional properties of these cells are not understood. Patients with SCA and those on HC therapy (SCAHC) were included in the study. SCAHC individuals presented significantly lower absolute numbers of eosinophils than SCA. Furthermore, SCAHC eosinophils demonstrated significantly lower adhesive properties, compared to SCA eosinophils. SCA and SCAHC eosinophils presented greater spontaneous migration when compared with control eosinophils. Baseline eosinophil peroxidase and reactive oxygen species release was higher for SCA individuals than for control individuals, as were plasma levels of eosinophil derived neurotoxin. SCAHC eosinophil degranulation was lower than that of SCA eosinophil degranulation. Eotaxin-1 and RANTES levels were higher in the plasma of SCA and SCAHC individuals, when compared with controls. These data suggest that eosinophils exist in an activated state in SCA and indicate that these cells play a role in the vaso-occlusive process. The exact mechanism by which HC may alter SCA eosinophil properties is not clear.

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“…Finally, AOP-RANTES activates CCR3 through the classic G proteincoupled pathway since treatment with pertussis toxin also abrogates the reactive oxygen species release induced by AOP-RANTES as well as by the other CCR3 ligands tested. On the other hand, Met-RANTES is not able to activate CCR3 and has been shown to inhibit eosinophil functions principally through CCR1 (35).…”

Section: Fig 3 Eotaxin-induced Heterologous Desensitization To Aop-mentioning

confidence: 99%

Differential Activation of CC Chemokine Receptors by AOP-RANTES

Elsner¹,

Mack²,

Brühl³

et al. 2000

Journal of Biological Chemistry

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RANTES (regulated on activation normal T cell expressed) has been found at elevated levels in biological fluids from patients with a wide range of allergic and autoimmune diseases and is able to attract several subtypes of leukocytes including eosinophils and monocytes into inflamed tissue. Amino-terminal modifications of RANTES produce receptor antagonists which are candidates for blocking this cellular recruitment. Met-RANTES has been shown to modulate inflammation in vivo, while AOP-RANTES is a potent inhibitor of R5 human immunodeficiency virus type 1 (HIV-1) strains and has been shown to down-modulate CCR5 and prevent recycling of the receptor. We have studied the effect of AOP-RANTES in eosinophil activation and have found that it is able to efficiently elicit eosinophil effector functions through CCR3, as measured by the release of reactive oxygen species and calcium mobilization, whereas Met-RANTES is inactive in these assays. AOP-RANTES is found to inhibit CCR3-mediated HIV-1 infection with moderate potency, in contrast to its potent inhibition of CCR5-mediated HIV-1 infection. Furthermore, we have investigated the abilities of these modified proteins to down-modulate CCR1 and CCR3 from the surface of monocytes and eosinophils. We show here that AOP-RANTES is much less effective than RANTES in down-modulation of CCR1. Surprisingly, recycling of CCR1 was minimal after incubation with RANTES while there was complete recycling with AOP-RANTES. In the case of CCR3, no significant difference was found between RANTES and AOP-RANTES in down-modulation and recycling. It therefore appears that trafficking of RANTES receptors follows different patterns, which opens up potential new targets for therapeutic intervention.Chemokines are chemotactic proteins that play a central role in immune and inflammatory responses by the attraction and activation of leukocytes. They can be divided into two major classes on the basis of the arrangement of the amino acid cysteine in the amino-terminal region: the CXC and CC chemokines, and two minor subclasses, each comprising a single member, the C and CX3C subclasses (1-3). Initially, it was generally accepted that the chemokine subclasses differ in their biological activity to stimulate different kinds of leukocytes, so that CXC chemokines are mediators of acute inflammation through neutrophil activation while the CC chemokines mediate chronic inflammation by attracting leukocytes such as eosinophils, monocytes, lymphocytes, basophils, and dendritic cells. However, this paradigm has recently been shown to have exceptions; for example, CXCR3 is expressed on activated T cells (4) and neutrophils can be activated by CC chemokines following stimulation with interferon-␥ (5).Chemokines mediate their effects by binding to cell-surface receptors that belong to the seven-transmembrane domain G protein-coupled receptor superfamily (1). More recently, chemokine receptors have been subject to intense scrutiny following the discovery that several of them are co-receptors for HIV 1 cell entr...

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The CC chemokine antagonist Met‐RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3

Cited by 121 publications

References 67 publications

CCR3 Is Required for Tissue Eosinophilia and Larval Cytotoxicity After Infection withTrichinella spiralis

CCR3 Is Required for Tissue Eosinophilia and Larval Cytotoxicity After Infection withTrichinella spiralis

Hydroxycarbamide reduces eosinophil adhesion and degranulation in sickle cell anaemia patients

Differential Activation of CC Chemokine Receptors by AOP-RANTES

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