title: A deficiency in the prostaglandin D2 receptor CRTH2 exacerbates adjuvant-induced joint inflammation.
abstract: Although the cyclooxygenase metabolites PGs are known to be involved in the progression of arthritis, the role of PGD2 remains unclear. In this study, we evaluated the contribution of signaling mediated through a PGD2 receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), in the progression of adjuvant-induced joint inflammation. Injection of CFA into the ankle joint stimulated PGD2 production and induced paw swelling in both CRTH2-naive (WT) and CRTH2(-/-) mice. CRTH2(-/-) mice presented more severe arthritic manifestations than did WT mice. Through bone marrow transplantation experiments between WT and CRTH2(-/-) mice, we showed that CRTH2 deficiency in bone marrow-derived immune cells is involved in disease progression. Morphological studies showed that CRTH2 deficiency accelerated the infiltration of macrophages into the inflamed paw. Consistent with this finding, we observed that treatment with the macrophage inactivator GdCl3 or the macrophage-depleting agent liposomal clodronate improved arthritis symptoms in CRTH2(-/-) mice. Adoptive transfer of CRTH2(-/-) macrophages exacerbated joint inflammation in WT mice. In addition, CRTH2 deficiency accelerated, whereas CRTH2 agonism inhibited, the expression of a macrophage-activating cytokine (GM-CSF) and a chemokine receptor (CXCR2) in CFA-treated peritoneal macrophages. Together, these observations demonstrate that PGD2-CRTH2 signaling plays a protective role in joint inflammation by attenuating the infiltration of macrophages.
authors.affiliation: Department of Animal Radiology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan;
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tsubosaka
authors.affiliation: Department of Animal Radiology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan;
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Advanced Medicine and Development, BML, Inc., Saitama 350-1101, Japan;
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirai
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan; and.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.affiliation: Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan; and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
authors.affiliation: Department of Animal Radiology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan; amurata@mail.ecc.u-tokyo.ac.jp.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Murata
mesh_terms: D000276:Adjuvants, Immunologic / Q000009:adverse effects; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism; D018450:Disease Progression; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015230:Prostaglandin D2 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000276:Adjuvants, Immunologic; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D015232:Dinoprostone; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor