A novel antagonist of CRTH2 blocks eosinophil release from bone marrow, chemotaxis and respiratory burst

J F Royer; P Schratl; S Lorenz; E Kostenis; T Ulven; R Schuligoi; B A Peskar; A Heinemann

doi:10.1111/j.1398-9995.2007.01452.x

A novel antagonist of CRTH2 blocks eosinophil release from bone marrow, chemotaxis and respiratory burst

J F Royer, P Schratl, S Lorenz, E Kostenis, T Ulven, R Schuligoi, B A Peskar, A Heinemann

40 Citations (Scopus)

Abstract

BACKGROUND: Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) has been revealed to be a novel receptor for prostaglandin (PG) D(2), which is a major mast cell product released during the allergic response. The aim of this study was to analyze the effects of a newly developed small molecule antagonist of CRTH2, Cay10471, on eosinophil function with respect to recruitment, respiratory burst and degranulation. METHODS: Chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils were determined using microBoyden chambers. Eosinophil release from bone marrow was investigated in the in situ perfused guinea pig hind limb preparation. Respiratory burst and degranulation were measured by flow cytometry. RESULTS: Cay10471 bound with high affinity to recombinant human and guinea pig CRTH2, but not DP, receptors. The antagonist prevented the PGD(2)-induced release of eosinophils from guinea pig bone marrow, and inhibited the chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils. Pretreatment with PGD(2) primed eosinophils for chemotaxis towards eotaxin, and this effect was prevented by Cay10471. In contrast, PGD(2) inhibited the C5a-induced up-regulation of CD63, a cellular marker of degranulation, in a Cay10471-sensitive manner. Finally, Cay10471 abolished the respiratory burst of eosinophils upon stimulation by PGD(2). CONCLUSION: These data further emphasize the importance of CRTH2 in eosinophil function and show that Cay10471 is a highly potent and selective antagonist of PGD(2)-induced eosinophil responses. Cay10471 might hence be a useful compound for the treatment of allergic diseases Udgivelsesdato: Dec

Original language	English
Journal	Allergy
Volume	62
Issue number	12
Pages (from-to)	1401-1409
Number of pages	9
ISSN	0105-4538
DOIs	https://doi.org/10.1111/j.1398-9995.2007.01452.x
Publication status	Published - 1 Dec 2007

Keywords

Animals
Bone Marrow
Carbazoles
Cell Degranulation
Cells, Cultured
Chemotaxis, Leukocyte
Eosinophils
Female
Guinea Pigs
Humans
Male
Receptors, Immunologic
Receptors, Prostaglandin
Respiratory Burst
Sulfonamides
Th2 Cells

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/j.1398-9995.2007.01452.x

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title = "A novel antagonist of CRTH2 blocks eosinophil release from bone marrow, chemotaxis and respiratory burst",

abstract = "BACKGROUND: Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) has been revealed to be a novel receptor for prostaglandin (PG) D(2), which is a major mast cell product released during the allergic response. The aim of this study was to analyze the effects of a newly developed small molecule antagonist of CRTH2, Cay10471, on eosinophil function with respect to recruitment, respiratory burst and degranulation. METHODS: Chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils were determined using microBoyden chambers. Eosinophil release from bone marrow was investigated in the in situ perfused guinea pig hind limb preparation. Respiratory burst and degranulation were measured by flow cytometry. RESULTS: Cay10471 bound with high affinity to recombinant human and guinea pig CRTH2, but not DP, receptors. The antagonist prevented the PGD(2)-induced release of eosinophils from guinea pig bone marrow, and inhibited the chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils. Pretreatment with PGD(2) primed eosinophils for chemotaxis towards eotaxin, and this effect was prevented by Cay10471. In contrast, PGD(2) inhibited the C5a-induced up-regulation of CD63, a cellular marker of degranulation, in a Cay10471-sensitive manner. Finally, Cay10471 abolished the respiratory burst of eosinophils upon stimulation by PGD(2). CONCLUSION: These data further emphasize the importance of CRTH2 in eosinophil function and show that Cay10471 is a highly potent and selective antagonist of PGD(2)-induced eosinophil responses. Cay10471 might hence be a useful compound for the treatment of allergic diseases Udgivelsesdato: Dec",

keywords = "Animals, Bone Marrow, Carbazoles, Cell Degranulation, Cells, Cultured, Chemotaxis, Leukocyte, Eosinophils, Female, Guinea Pigs, Humans, Male, Receptors, Immunologic, Receptors, Prostaglandin, Respiratory Burst, Sulfonamides, Th2 Cells",

author = "Royer, {J F} and P Schratl and S Lorenz and E Kostenis and T Ulven and R Schuligoi and Peskar, {B A} and A Heinemann",

year = "2007",

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doi = "10.1111/j.1398-9995.2007.01452.x",

language = "English",

volume = "62",

pages = "1401--1409",

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TY - JOUR

T1 - A novel antagonist of CRTH2 blocks eosinophil release from bone marrow, chemotaxis and respiratory burst

AU - Royer, J F

AU - Schratl, P

AU - Lorenz, S

AU - Kostenis, E

AU - Ulven, T

AU - Schuligoi, R

AU - Peskar, B A

AU - Heinemann, A

PY - 2007/12/1

Y1 - 2007/12/1

N2 - BACKGROUND: Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) has been revealed to be a novel receptor for prostaglandin (PG) D(2), which is a major mast cell product released during the allergic response. The aim of this study was to analyze the effects of a newly developed small molecule antagonist of CRTH2, Cay10471, on eosinophil function with respect to recruitment, respiratory burst and degranulation. METHODS: Chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils were determined using microBoyden chambers. Eosinophil release from bone marrow was investigated in the in situ perfused guinea pig hind limb preparation. Respiratory burst and degranulation were measured by flow cytometry. RESULTS: Cay10471 bound with high affinity to recombinant human and guinea pig CRTH2, but not DP, receptors. The antagonist prevented the PGD(2)-induced release of eosinophils from guinea pig bone marrow, and inhibited the chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils. Pretreatment with PGD(2) primed eosinophils for chemotaxis towards eotaxin, and this effect was prevented by Cay10471. In contrast, PGD(2) inhibited the C5a-induced up-regulation of CD63, a cellular marker of degranulation, in a Cay10471-sensitive manner. Finally, Cay10471 abolished the respiratory burst of eosinophils upon stimulation by PGD(2). CONCLUSION: These data further emphasize the importance of CRTH2 in eosinophil function and show that Cay10471 is a highly potent and selective antagonist of PGD(2)-induced eosinophil responses. Cay10471 might hence be a useful compound for the treatment of allergic diseases Udgivelsesdato: Dec

AB - BACKGROUND: Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) has been revealed to be a novel receptor for prostaglandin (PG) D(2), which is a major mast cell product released during the allergic response. The aim of this study was to analyze the effects of a newly developed small molecule antagonist of CRTH2, Cay10471, on eosinophil function with respect to recruitment, respiratory burst and degranulation. METHODS: Chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils were determined using microBoyden chambers. Eosinophil release from bone marrow was investigated in the in situ perfused guinea pig hind limb preparation. Respiratory burst and degranulation were measured by flow cytometry. RESULTS: Cay10471 bound with high affinity to recombinant human and guinea pig CRTH2, but not DP, receptors. The antagonist prevented the PGD(2)-induced release of eosinophils from guinea pig bone marrow, and inhibited the chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils. Pretreatment with PGD(2) primed eosinophils for chemotaxis towards eotaxin, and this effect was prevented by Cay10471. In contrast, PGD(2) inhibited the C5a-induced up-regulation of CD63, a cellular marker of degranulation, in a Cay10471-sensitive manner. Finally, Cay10471 abolished the respiratory burst of eosinophils upon stimulation by PGD(2). CONCLUSION: These data further emphasize the importance of CRTH2 in eosinophil function and show that Cay10471 is a highly potent and selective antagonist of PGD(2)-induced eosinophil responses. Cay10471 might hence be a useful compound for the treatment of allergic diseases Udgivelsesdato: Dec

KW - Animals

KW - Bone Marrow

KW - Carbazoles

KW - Cell Degranulation

KW - Cells, Cultured

KW - Chemotaxis, Leukocyte

KW - Eosinophils

KW - Female

KW - Guinea Pigs

KW - Humans

KW - Male

KW - Receptors, Immunologic

KW - Receptors, Prostaglandin

KW - Respiratory Burst

KW - Sulfonamides

KW - Th2 Cells

U2 - 10.1111/j.1398-9995.2007.01452.x

DO - 10.1111/j.1398-9995.2007.01452.x

M3 - Journal article

SN - 0105-4538

VL - 62

SP - 1401

EP - 1409

JO - Allergy: European Journal of Allergy and Clinical Immunology

JF - Allergy: European Journal of Allergy and Clinical Immunology

IS - 12

ER -

A novel antagonist of CRTH2 blocks eosinophil release from bone marrow, chemotaxis and respiratory burst

Abstract

Keywords

UN SDGs

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