title: Identification of an S100A8 Receptor Neuroplastin-β and its Heterodimer Formation with EMMPRIN.
abstract: We previously reported a positive feedback loop between S100A8/A9 and proinflammatory cytokines mediated by extracellular matrix metalloproteinase inducer, an S100A9 receptor. Here, we identify neuroplastin-β as an unreported S100A8 receptor. Neuroplastin-β and extracellular matrix metalloproteinase inducer form homodimers and a heterodimer, and they are co-localized on the surface of cultured normal human keratinocytes. Knockdown of both receptors suppressed cell proliferation and proinflammatory cytokine induction. Upon stimulation with S100A8, neuroplastin-β recruited GRB2 and activated extracellular signal-regulated kinase, resulting in keratinocyte proliferation. Keratinocyte proliferation in response to inflammatory stimuli was accelerated in involucrin promoter-driven S100A8 transgenic mice. Further, S100A8 and S100A9 were strongly up-regulated and co-localized in lesional skin of atopic dermatitis patients. Our results indicate that neuroplastin-β and extracellular matrix metalloproteinase inducer form a functional heterodimeric receptor for S100A8/A9 heterodimer, followed by recruitment of specific adaptor molecules GRB2 and TRAF2, and this signaling pathway is involved in activation of both keratinocyte proliferation and skin inflammation in atopic skin. Suppression of this pathway might have potential for treatment of skin diseases associated with chronic inflammation such as atopic dermatitis.
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Kita-ku, Okayama, Japan. Electronic address: masa-s@md.okayama-u.ac.jp.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sakaguchi
authors.affiliation: Department of Dermatology, Tokyo Medical University, Nishi-Shinjuku, Shinjuku-ku, Tokyo, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Miyai
authors.affiliation: Department of Dermatology, Tokyo Medical University, Nishi-Shinjuku, Shinjuku-ku, Tokyo, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Dermatology, Tokyo Medical University, Nishi-Shinjuku, Shinjuku-ku, Tokyo, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Hiruma
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Murata
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Kinoshita
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: I Made
authors.initials: IM
authors.lastname: Winarsa Ruma
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Endy Widya
authors.initials: EW
authors.lastname: Putranto
authors.affiliation: Faculty of Science and Technology, Division of Molecular Science, Gunma University, Tenjin-cho, Kiryu-shi, Gunma, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Morizane
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Kita-ku, Okayama, Japan.
authors.forename: Nam-Ho
authors.initials: NH
authors.lastname: Huh
authors.affiliation: Department of Dermatology, Tokyo Medical University, Nishi-Shinjuku, Shinjuku-ku, Tokyo, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Tsuboi
authors.affiliation: Department of Dermatology, Tokyo Medical University, Nishi-Shinjuku, Shinjuku-ku, Tokyo, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hibino
mesh_terms: D000818:Animals; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D040501:Calgranulin A / Q000096:biosynthesis* / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D040501:Calgranulin A; D008562:Membrane Glycoproteins; C086145:S100a8 protein, mouse; C577174:neuroplastin protein, mouse; D051926:Basigin