BACKGROUND AND AIMS: Prostaglandin [PG] D2 activates two receptors, DP and CRTH2. Antagonism of CRTH2 has been shown to promote anti-allergic and anti-inflammatory effects. We investigated whether CRTH2 may play a role in Crohn's disease [CD], focusing on eosinophils which are widely present in the inflamed mucosa of CD patients and express both receptors. METHODS: Using the 2,4,6-trinitrobenzenesulfonic acid [TNBS]-induced colitis model, involvement of CRTH2 in colitis was investigated by pharmacological antagonism, immunohistochemistry, Western blotting, immunoassay, and leukocyte recruitment. Chemotactic assays were performed with isolated human eosinophils. Biopsies and serum samples of CD patients were examined for presence of CRTH2 and ligands, respectively. RESULTS: High amounts of CRTH2-positive cells, including eosinophils, are present in the colonic mucosa of mice with TNBS colitis and in human CD. The CRTH2 antagonist OC-459, but not the DP antagonist MK0524, reduced inflammation scores and decreased TNF-α, IL-1β, and IL-6 as compared with control mice. OC-459 inhibited recruitment of eosinophils into the colon and also inhibited CRTH2-induced chemotaxis of human eosinophils in vitro. Eosinophil-depleted ΔdblGATA knockout mice were less sensitive to TNBS-induced colitis, whereas IL-5 transgenic mice with lifelong eosinophilia were more severely affected than wild types. In addition, we show that serum levels of PGD2 and Δ(12)-PGJ2 were increased in CD patients as compared with control individuals. CONCLUSIONS: CRTH2 plays a pro-inflammatory role in TNBS-induced colitis. Eosinophils contribute to the severity of the inflammation, which is improved by a selective CRTH2 antagonist. CRTH2 may, therefore, represent an important target in the pharmacotherapy of CD.
BACKGROUND AND AIMS: Prostaglandin [PG] D2 activates two receptors, DP and CRTH2. Antagonism of CRTH2 has been shown to promote anti-allergic and anti-inflammatory effects. We investigated whether CRTH2 may play a role in Crohn's disease [CD], focusing on eosinophils which are widely present in the inflamed mucosa of CD patients and express both receptors. METHODS: Using the 2,4,6-trinitrobenzenesulfonic acid [TNBS]-induced colitis model, involvement of CRTH2 in colitis was investigated by pharmacological antagonism, immunohistochemistry, Western blotting, immunoassay, and leukocyte recruitment. Chemotactic assays were performed with isolated human eosinophils. Biopsies and serum samples of CD patients were examined for presence of CRTH2 and ligands, respectively. RESULTS: High amounts of CRTH2-positive cells, including eosinophils, are present in the colonic mucosa of mice with TNBS colitis and in human CD. The CRTH2 antagonist OC-459, but not the DP antagonist MK0524, reduced inflammation scores and decreased TNF-α, IL-1β, and IL-6 as compared with control mice. OC-459 inhibited recruitment of eosinophils into the colon and also inhibited CRTH2-induced chemotaxis of human eosinophils in vitro. Eosinophil-depleted ΔdblGATA knockout mice were less sensitive to TNBS-induced colitis, whereas IL-5 transgenic mice with lifelong eosinophilia were more severely affected than wild types. In addition, we show that serum levels of PGD2 and Δ(12)-PGJ2 were increased in CD patients as compared with control individuals. CONCLUSIONS: CRTH2 plays a pro-inflammatory role in TNBS-induced colitis. Eosinophils contribute to the severity of the inflammation, which is improved by a selective CRTH2 antagonist. CRTH2 may, therefore, represent an important target in the pharmacotherapy of CD.
Authors: R Pettipher; M G Hunter; C M Perkins; L P Collins; T Lewis; M Baillet; J Steiner; J Bell; M A Payton Journal: Allergy Date: 2014-07-14 Impact factor: 13.146
Authors: F G Gervais; R P Cruz; A Chateauneuf; S Gale; N Sawyer; F Nantel; K M Metters; G P O'neill Journal: J Allergy Clin Immunol Date: 2001-12 Impact factor: 10.793
Authors: Petra Schratl; Julia F Royer; Evi Kostenis; Trond Ulven; Eva M Sturm; Maria Waldhoer; Gerald Hoefler; Rufina Schuligoi; Irmgard Th Lippe; Bernhard A Peskar; Akos Heinemann Journal: J Immunol Date: 2007-10-01 Impact factor: 5.422
Authors: E D Tait Wojno; L A Monticelli; S V Tran; T Alenghat; L C Osborne; J J Thome; C Willis; A Budelsky; D L Farber; D Artis Journal: Mucosal Immunol Date: 2015-04-08 Impact factor: 7.313
Authors: J F Royer; P Schratl; S Lorenz; E Kostenis; T Ulven; R Schuligoi; B A Peskar; A Heinemann Journal: Allergy Date: 2007-08-21 Impact factor: 13.146
Authors: Claire M Smyth; Nadim Akasheh; Sara Woods; Elaine Kay; Ross K Morgan; Margaret A Thornton; Anthony O'Grady; Robert Cummins; Orla Sheils; Peter Smyth; Gerald J Gleich; Frank M Murray; Richard W Costello Journal: PLoS One Date: 2013-05-22 Impact factor: 3.240
Authors: Carina Hasenoehrl; David Feuersinger; Eva M Sturm; Thomas Bärnthaler; Ellen Heitzer; Ricarda Graf; Magdalena Grill; Martin Pichler; Stephan Beck; Lee Butcher; Dominique Thomas; Nerea Ferreirós; Rufina Schuligoi; Caroline Schweiger; Johannes Haybaeck; Rudolf Schicho Journal: Int J Cancer Date: 2017-09-21 Impact factor: 7.396
Authors: Elizabeth A Jacobsen; David J Jackson; Enrico Heffler; Sameer K Mathur; Albert J Bredenoord; Ian D Pavord; Praveen Akuthota; Florence Roufosse; Marc E Rothenberg Journal: Annu Rev Immunol Date: 2021-03-01 Impact factor: 28.527