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.
This work was supported by a Research Fellowship for Young Scientists (to Y.T.) and by the Program for Promotion of Basic and Applied Research for Innovations in Bio-Oriented Industry; the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry; a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science; The Uehara Memorial Foundation; The Takeda Science Foundation; and The Japan Health Foundation (to T.M.).
The online version of this article contains supplemental material.
- Received December 30, 2013.
- Accepted October 4, 2014.
- Copyright © 2014 by The American Association of Immunologists, Inc.