title: TIARP attenuates autoantibody-mediated arthritis via the suppression of neutrophil migration by reducing CXCL2/CXCR2 and IL-6 expression.
abstract: TNFα-induced adipose-related protein (TIARP) is a six-transmembrane protein expressed on macrophages, neutrophils and synoviocytes. We reported recently that mice deficient in TIARP (TIARP-/-) spontaneously develop arthritis and are highly susceptible to collagen-induced arthritis (CIA) with enhanced interleukin (IL)-6 production. However, the effects of TIARP on neutrophils and fibroblast-like synoviocytes (FLS) have not been elucidated. We analyzed the roles of TIARP in K/BxN serum transfer model using TIARP-/-mice. Arthritis in TIARP-/-mice transferred with K/BxN serum was significantly exacerbated compared with WT mice. We characterized the differences in neutrophils between wild-type (WT) and TIARP-/-mice by DNA microarray. Overexpression of CXCR1 and CXCR2 was noted in TIARP-/-neutrophils. Neutrophils of TIARP-/-mice showed strong migration activity, which was markedly facilitated by CXCL2 in vitro and in vivo. Moreover, enhanced production of CXCL2 and IL-6 and cell proliferation was noted in TIARP-/-TNFα-stimulated FLS. Blockade of IL-6R significantly attenuated serum-transferred TIARP-/-arthritis with diminished neutrophil recruitment in joints. Our findings suggested that TIARP independently down-regulated CXCL2 and IL-6 production by FLS, and the expression of chemokine receptors (CXCR1 and CXCR2) in neutrophils, with resultant reduction of neutrophil migration into arthritic joints.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Umeda
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Takai
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
authors.forename: Hoshimi
authors.initials: H
authors.lastname: Kawaguchi
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ebe
authors.affiliation: Chugai Pharmaceuticals Co., Ltd. Fuji Gotemba Research Labs, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Chugai Pharmaceuticals Co., Ltd. Fuji Gotemba Research Labs, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Segawa
authors.affiliation: Department of Anatomy and Embryology, Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, 305-8575, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics / Q000473:pathology*; D001323:Autoantibodies / Q000378:metabolism*; D002465:Cell Movement; D054426:Chemokine CXCL2 / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005121:Extremities / Q000473:pathology; D005347:Fibroblasts / Q000473:pathology; D063990:Gene Ontology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D008822:Mice, Transgenic; D009500:Neutralization Tests; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D044967:Serum; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D001323:Autoantibodies; D054426:Chemokine CXCL2; D016207:Cytokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D008565:Membrane Proteins; D023063:Receptors, Interleukin-8B; C436323:Tiarp protein, mouse; D014409:Tumor Necrosis Factor-alpha