Development of new therapies and eluciation of pathomechanisms for psoriatic arthritis wich focusing on IL-36 and TLR-4

• Project/Area Number: 16K15546
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Fujita Health University
• Principal Investigator: SUGIURA Kazumitsu 藤田保健衛生大学, 医学部, 教授 (70335032)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2016: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 関節症性乾癬 / IL-36 / TLR-4 / リポ多糖 / IL36RNノックアウトマウス / 膿疱性乾癬 / TLR4 / モデルマウス / 骨髄由来間葉系細胞

Outline of Final Research Achievements

Bone erosion or joint deformity emerges in 2 years in 50% of patients with psoriatic arthritis (PsA). Dermatologist should make diagnosis and treat early PsA because 70% of patients with PsA shows skin lesions preceding arthritis. But pathomechanisms of PsA remains unknown. In this study, we focused on Toll-like receptor-4(TLR-4) for the pathomechanisms. Lipopolysaccharide (LPS), a TLR-4 ligand, was injected on a foot pad of IL36RN knock out (KO) mouse. Then, outstanding swelling and thickness of foot was observed in the IL36RN KO mouse compering in the wild mouse. In conclusion we made a PsA model using the IL36RN KO mouse with TLR-4 ligand injection on the food pad. Furthermore, we proved that TLR-4 inhibitor ameliorates the symptom of the PsA model.

Research Products

• [Journal Article] Localization of collagen type 5 in the papillary dermis and its role in maintaining stem cell functions. (2018)
  • Author(s): Hasebe Y, Hasegawa S, Date Y, Nakata S, Yagami A, Iwata Y, Sugiura K, Akamatsu H.
  • Journal Title: J Dermatol Sci Volume: 89 Issue: 2 Pages: 205-207
  • DOI: 10.1016/j.jdermsci.2017.10.005
  • NAID: 120006477489
  • Peer Reviewed
• [Journal Article] Trichothiodystrophy, complementation group A complicated with squamous cell carcinoma. (2018)
  • Author(s): Takeichi T, Tomimura S, Okuno Y, Hamada M, Kono M, Sugiura K, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Volume: 32 Issue: 2
  • DOI: 10.1111/jdv.14531
  • Peer Reviewed
• [Journal Article] A novel IFIH1 mutation in the pincer domain underlies the clinical features of both Aicardi-Goutières and Singleton-Merten syndromes in a single patient. (2018)
  • Author(s): Takeichi T, Katayama C, Tanaka T, Okuno Y, Murakami N, Kono M, Sugiura K, Aoyama Y, Akiyama M.
  • Journal Title: Br J Dermatol Volume: 178 Issue: 2 Pages: e111-e113
  • DOI: 10.1111/bjd.15869
  • Peer Reviewed
• [Journal Article] Multiple keratotic papules and plaques on the trunk in Cowden’s disease with MALT lymphoma. (2018)
  • Author(s): Mizuno S, Takeichi T, Sato J, Nakamura M, Goto H, Sugiura K, Akiyama M.
  • Journal Title: J Dermatol Volume: 45 Issue: 2 Pages: 238-240
  • DOI: 10.1111/1346-8138.13851
  • NAID: 120006473545
  • Peer Reviewed
• [Journal Article] Bilateral anterior uveitis and unilateral facial palsy due to ipilimumab for metastatic melanoma in an individual with human leukocyte antigen DR4: A case report. (2018)
  • Author(s): Numata S, Iwata Y, Okumura R, Arima M, Kobayashi T, Watanabe S, Suzuki K, Horiguchi M, Sugiura K.
  • Journal Title: J Dermatol Volume: 45 Issue: 1 Pages: 113-114
  • DOI: 10.1111/1346-8138.13779
  • Peer Reviewed
• [Journal Article] Biallelic Mutations in KDSR Disrupt Ceramide Synthesis and Result in a Spectrum of Keratinization Disorders Associated with Thrombocytopenia. (2017)
  • Author(s): Takeichi T, Torrelo A, Lee JYW, Ohno Y, Lozano ML, Kihara A, Liu L, Yasuda Y, Ishikawa J, Murase T, Rodrigo AB, Fernández-Crehuet P, Toi Y, Mellerio J, Rivera J, Vicente V, Kelsell DP, Nishimura Y, Okuno Y, Kojima D, Ogawa Y, Sugiura K, Simpson MA, McLean WHI, Akiyama M, McGrath JA.
  • Journal Title: J Invest Dermatol. Volume: 137 Issue: 11 Pages: 2344-2353
  • DOI: 10.1016/j.jid.2017.06.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autoinflammatory keratinization diseases. (2017)
  • Author(s): Akiyama M, Takeichi T, McGrath JA, Sugiura K.
  • Journal Title: J Allergy Clin Immunol. Volume: 140 Issue: 6 Pages: 1545-1547
  • DOI: 10.1016/j.jaci.2017.05.019
  • NAID: 120006473509
  • Peer Reviewed
• [Journal Article] Successful treatment of continuous intra-arterial administration of prostaglandin E1, urokinase, and heparin for intractable digital ulcers by upper-extremity arterial occlusion in diffuse cutaneous systemic sclerosis patient. (2017)
  • Author(s): Numata S, Iwata Y, Kobayashi M, Sato T, Sugiura K.
  • Journal Title: J Dermatol Volume: 44 Issue: 10
  • DOI: 10.1111/1346-8138.13935
  • Peer Reviewed
• [Journal Article] Granulocyte and monocyte apheresis can control juvenile generalized pustular psoriasis with mutation of IL36RN. (2017)
  • Author(s): Koike Y, Okubo M, Kiyohara T, Fukuchi R, Sato Y, Kuwatsuka S, Takeichi T, Akiyama M, Sugiura K, Utani A.
  • Journal Title: Br J Dermatol. Volume: 177 Issue: 6 Pages: 1732-1736
  • DOI: 10.1111/bjd.15509
  • Peer Reviewed
• [Journal Article] Retention of pigment stem cells in Rhododenol-induced leukoderma: pathological investigation of 11 patients. (2017)
  • Author(s): Watanabe S, Yagami A, Iwata Y, Nagai A, Kuroda M, Sugiura K, Matsunaga K.
  • Journal Title: J Dermatol Volume: 44 Issue: 7
  • DOI: 10.1111/1346-8138.13885
  • Peer Reviewed
• [Journal Article] Autosomal dominant familial generalized pustular psoriasis caused by a CARD14 mutation. (2017)
  • Author(s): Takeichi T, Kobayashi A, Ogawa E, Okuno Y, Kataoka S, Kono M, Sugiura K, Okuyama R, Akiyama M.
  • Journal Title: Br J Dermatol. Volume: 177 Issue: 4 Pages: e133-e135
  • DOI: 10.1111/bjd.15442
  • Peer Reviewed
• [Journal Article] Toll-like receptor 4 antagonist TAK-242 inhibits autoinflammatory symptoms in DITRA. (2017)
  • Author(s): Shibata A, Sugiura K, Furuta Y, Mukumoto Y, Kaminuma O, Akiyama M.
  • Journal Title: J Autoimmun Volume: 80 Pages: 28-38
  • DOI: 10.1016/j.jaut.2017.01.007
  • NAID: 120006331817
  • Peer Reviewed
• [Journal Article] Enhancement of Individual Differences in Proliferation and Differentiation Potentials of Aged Human Adipose-Derived Stem Cells. (2017)
  • Author(s): Kawagishi-Hotta M, Hasegawa S, Igarashi T, Yamada T, Takahashi M, Numata S, Kobayashi T, Iwata Y, Arima M, Yamamoto N, Yagami A, Nakata S, Uzawa T, Matsunaga K, Sugiura K, Akamatsu H.
  • Journal Title: Regenerative Therapy Volume: 6 Pages: 29-40
  • Peer Reviewed
• [Journal Article] Dermal CD271+ cells are closely associated with regeneration of the dermis in the wound healing process. (2017)
  • Author(s): Iwata Y, Hasebe Y, Hasegawa S, Nakata S, Yagami A, Matsunaga K, Sugiura K, Akamatsu H.
  • Journal Title: Acta Derm Venereol Volume: 177 Issue: 5 Pages: 593-600
  • DOI: 10.2340/00015555-2624
  • Peer Reviewed / Open Access
• [Journal Article] Case report of multiple pustules of the bilateral lower limbs caused by a granulocyte colony-stimulating factor–producing solid pseudopapillary tumour of the pancreas. (2017)
  • Author(s): Iwata Y, Kobayashi T, Kuroda M, Mizoguchi Y, Arima M, Numata S, Watanabe S, Yagami A, Matsunaga K, Sugiura K.
  • Journal Title: Br J Dermatol Volume: 177 Issue: 4 Pages: 1122-1126
  • DOI: 10.1111/bjd.15219
  • Peer Reviewed
• [Journal Article] Fracture of pili torti results from abnormal sinusoidal morphology in the cuticle layers and loose keratin intermediate filaments in the cortex. (2017)
  • Author(s): Marubashi Y, Yanagishita T, Muto J, Taguchi N, Sugiura K, Kawamoto Y, Akiyama M, Watanabe D.
  • Journal Title: J Dermatol Volume: 44 Issue: 4 Pages: 455-458
  • DOI: 10.1111/1346-8138.13700
  • Peer Reviewed
• [Journal Article] Mutational analysis of 29 patients with autosomal recessive woolly hair and hypotrichosis: LIPH mutations are extremely predominant in autosomal recessive woolly hair and hypotrichosis in Japan. (2017)
  • Author(s): Takeichi T, Tanahashi K, Taki T, Kono M, Sugiura K, Akiyama M.
  • Journal Title: Br J Dermatol Volume: 177 Issue: 1 Pages: 290-292
  • DOI: 10.1111/bjd.15070
  • Peer Reviewed
• [Journal Article] Certolizumab pegol, a pegylated anti-TNF-α antagonist, caused de novo-onset palmoplantar pustulosis followed by generalized pustular psoriasis in a patient with rheumatoid arthritis. (2017)
  • Author(s): Koizumi H, Tokuriki A, Oyama N, Ido H, Sugiura K, Akiyama M, Hasegawa M.
  • Journal Title: J Dermatol Volume: 44 Issue: 6 Pages: 723-724
  • DOI: 10.1111/1346-8138.13530
  • Peer Reviewed
• [Journal Article] Impetigo Herpetiformis Complicated with Intrauterine Growth Restriction Treated Successfully with Granulocyte and Monocyte Apheresis. (2017)
  • Author(s): Saito-Sasaki N, Izu K, Sawada Y, Hino R, Nakano R, Shimajiri S, Nishimura I, Nakamura H, Sugiura K, Nakamura M.
  • Journal Title: Acta Derm Venereol Volume: 97 Issue: 3 Pages: 410-411
  • DOI: 10.2340/00015555-2527
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Striate palmoplantar keratoderma showing transgrediens in a patient harboring heterozygous nonsense mutations in both DSG1 and SERPINB7. (2017)
  • Author(s): Fukaura R, Takeichi T, Okuno Y, Kojima D, Kono M, Sugiura K, Suga Y, Akiyama M.
  • Journal Title: Acta Derm Venereol Volume: 97 Issue: 3 Pages: 399-401
  • DOI: 10.2340/00015555-2553
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Punctate Palmoplantar Keratoderma Type 1 with a Novel AAGAB Frameshift Mutation: intrafamilial phenotype variation due to aging. (2017)
  • Author(s): Kono M, Fukai K, Shimizu N, Nagao J, Takeichi T, Tsuruta D, Sugiura K, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 31 Issue: 3
  • DOI: 10.1111/jdv.13906
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ripple-pattern lichen amyloidosis in a case of ichthyosis vulgaris with a novel FLG mutation. (2017)
  • Author(s): Kono M, Nishida K, Takeichi T, Sugiura K, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 31 Issue: 2
  • DOI: 10.1111/jdv.13877
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A case of epidermolytic ichthyosis showing a very mild phenotype due to a novel tail extension mutation in KRT10. (2017)
  • Author(s): Kono M, Fukai K, Omura R, Sugawara K, Tsuruta D, K Sugiura K, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 31 Issue: 2
  • DOI: 10.1111/jdv.13729
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pityriasis rubra pilaris type V as an auto inflammatory disease by CARD14 mutations. (2017)
  • Author(s): Takeichi T, Sugiura K, Nomura T, Sakamoto T, Ogawa Y, Oiso N, Futei Y, Fujisaki A, Koizumi A, Aoyama Y, Nakajima K, Hatano Y, Hayashi K, Akemi Ishida-Yamamoto A, Fujiwara S, Sano S, Iwatsuki K, Kawada A, Suga Y, Shimizu H, McGrath JA, Akiyama M.
  • Journal Title: JAMA Dermatol Volume: 153 Issue: 1 Pages: 66-70
  • DOI: 10.1001/jamadermatol.2016.3601
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A newly revealed IL36RN mutation in sibling cases complements our IL36RN mutation statistics for generalized pustular psoriasis. (2017)
  • Author(s): Takeichi T, Togawa Y, Taniguchi R, Okuno Y, Kono M, Matsue H, Sugiura K, Akiyama M.
  • Journal Title: J Dermatol Sci Volume: 85 Issue: 1 Pages: 58-60
  • DOI: 10.1016/j.jdermsci.2016.10.009
  • NAID: 120006305585
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel and recurrent ATP2A2 mutations in Japanese patients with Darier’s disease (2016)
  • Author(s): Noda K, Takeichi T, Okuno Y, Takama H, Miura S, Kagami S, Hino H, Nakamura Y, Fujio Y, Konohana I, Otani A, Mukai H, Sugiura K, Akiyama M.
  • Journal Title: Nagoya Journal of Medical Science Volume: 78 Issue: 4 Pages: 485-492
  • DOI: 10.18999/nagjms.78.4.485
  • NAID: 120005889988
  • ISSN: 2186-3326
  • URL: https://nagoya.repo.nii.ac.jp/records/22949
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Darier’s Disease Complicated by Schizophrenia Caused by a Novel ATP2A2 Mutation (2016)
  • Author(s): Takeichi T, Sugiura K, Nakamura Y, Fujio Y, Konohana I, Akiyama M.
  • Journal Title: Acta Derm Venereol Volume: in press Issue: 7 Pages: 993-994
  • DOI: 10.2340/00015555-2422
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Epididymitis with epididymal cysts indicating IgA vasculitis in an adult. (2016)
  • Author(s): Nanbu A, Sugiura K, Sassa N, Akiyama M.
  • Journal Title: Acta Derm Venereol Volume: 96 Issue: 7 Pages: 985-986
  • DOI: 10.2340/00015555-2382
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hyperpigmentation over the metacarpophalangeal joints and the malleoli in a case of hyaline fibromatosis syndrome with ANTXR2 mutations. (2016)
  • Author(s): Sugiura K, Ohno A, Kono M, Kitoh H, Itomi K, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Venereol. Volume: - Issue: 10 Pages: 44-46
  • DOI: 10.1111/jdv.13290
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A 45-year-old woman with Ehlers-Danlos syndrome caused by dermatan 4-O-sulfotransferase-1 deficiency: implications of dermatan sulfate depletion on early aging. (2016)
  • Author(s): Kono M, Hasegawa-Murakami Y, Sugiura K, Ono M, Toriyama K, Miyake N, Hatamochi A, Kamei Y, Kosho T, Akiyama M.
  • Journal Title: Acta Derm Venereol. Volume: - Pages: 1-2
  • DOI: 10.2340/00015555-2390
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Erythrokeratoderma Variabilis Caused by p.Gly45Glu in Connexin 31: Importance of the First Extracellular Loop Glycine Residue for Gap Junction Function (2016)
  • Author(s): Takeichi T, Sugiura K, Hsu CK, Nomura T, Takama H, Simpson MA, Shimizu H, McGrath JA, Akiyama M.
  • Journal Title: Acta Derm Venereol Volume: 96 Issue: 4 Pages: 557-559
  • DOI: 10.2340/00015555-2307
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Lipodystrophia centrifugalis abdominalis infantilis accompanied by idiopathic encephalopathy. (2016)
  • Author(s): Kaibuchi-Noda K, Sugiura K, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 30 Issue: 5 Pages: 862-864
  • DOI: 10.1111/jdv.13031
  • NAID: 120005844134
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dyschromatosis symmetrica hereditaria and Aicardi-Goutires syndrome 6 are phenotypic variants caused by ADAR1 mutations. (2016)
  • Author(s): Kono M, Matsumoto F, Suzuki Y, Suganuma M, Saitsu H, Ito Y, Fujiwara S, Matsumoto K, Moriwaki S, Matsumoto N, Tomita Y, Sugiura K, Akiyama M.
  • Journal Title: J Invest Dermatol. Volume: 136 Issue: 4 Pages: 875-8
  • DOI: 10.1016/j.jid.2015.12.034
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cutaneous Manifestations in Dermatomyositis: Key Clinical and Serological Features-a Comprehensive Review (2016)
  • Author(s): Muro Y, Sugiura K, Akiyama M.
  • Journal Title: Clin Rev Allergy Immunol Volume: 51 Pages: 293-302
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 自己炎症性角化症：乾癬と自己炎症 (2017)
  • Author(s): 杉浦一充
  • Organizer: 岡山県医師会皮膚科部会 岡山市医師会皮膚科・泌尿器科専門医会 学術講演会
  • Invited
• [Presentation] 皮膚科の自己炎症性疾患 DITRAとCAMPS (2017)
  • Author(s): 杉浦一充
  • Organizer: 第44回皮膚かたち研究学会学術大会
  • Invited
• [Presentation] 分子病態解明が進む膿疱性乾癬の治療標的 (2017)
  • Author(s): 杉浦一充
  • Organizer: 第81回日本皮膚科学会東部支部学術大会
  • Invited
• [Presentation] 膿疱性乾癬の病態と治療標的 (2017)
  • Author(s): 杉浦一充
  • Organizer: 日本皮膚科学会東北六県合同地方会学術大会第378回例会
  • Invited
• [Presentation] DITRAモデルマウスの解錫と毛孔性紅色粃糠疹の遺伝学的解析 (2017)
  • Author(s): 杉浦一充
  • Organizer: 第116回日本皮膚科学会総会
  • Invited
• [Presentation] 膿疱性乾癬の病因と臨床 (2017)
  • Author(s): 杉浦一充
  • Organizer: 第116回日本皮膚科学会総会
  • Invited
• [Presentation] 膿疱性乾癬のバイオマーカーと治療標的 (2017)
  • Author(s): 杉浦一充
  • Organizer: 2017年度生命科学系学会合同年次大会(第40回日本分子生物学会年会・第90回日本生化学会大会)
  • Invited
• [Presentation] Genetic background of generalized pustular psoriasis (2016)
  • Author(s): Kazumitsu Sugiura
  • Organizer: International congress of human genetics
  • Place of Presentation: 京都市（京都国際会館）
  • Int'l Joint Research / Invited
• [Presentation] 遺伝性の乾癬：DITRAとCAMPS (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: 横浜市（パシフィコ横浜）
  • Invited
• [Presentation] 汎発性膿疱性乾癬における膿疱形成のメカニズム (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第115回日本皮膚科学会総会
  • Place of Presentation: 京都市（京都国際会館）
  • Invited
• [Presentation] 意外な遺伝性皮膚疾患 (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第276回日本皮膚科学会東海地方会
  • Place of Presentation: 名古屋市(大正製薬(株)中日本支店)
  • Invited
• [Presentation] インターロイキン36受容体拮抗因子欠損と加齢が身体に及ぼす影響の検討 (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第12回加齢皮膚医学研究会
  • Place of Presentation: 神戸市(兵庫県医師会館)
  • Invited
• [Presentation] Genetic background of pustular psoriasis (2016)
  • Author(s): Kazumitsu Sugiura
  • Organizer: Asia-Pacific Combined Dermatology Research Conference
  • Place of Presentation: Noosa, Australia (Sofitel Pacific Resort Noosa Hotel)
  • Int'l Joint Research / Invited
• [Presentation] 自己炎症性疾患としての膿疱性乾癬 (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第31回日本乾癬学会学術大会
  • Place of Presentation: 宇都宮市(ホテル東日本宇都宮)
  • Invited
• [Presentation] IL-36R阻害剤 (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第31回日本乾癬学会学術大会
  • Place of Presentation: 宇都宮市(ホテル東日本宇都宮)
  • Invited
• [Presentation] 皮膚科の自己炎症性疾患；DITRAとCAMPS (2016)
  • Author(s): 杉浦 一充
  • Organizer: 日本皮膚科学会愛媛地方会第64回学術大会
  • Place of Presentation: 松山市(いよてつ会館)
  • Invited
• [Presentation] Genetic background of pustular psoriasis (2016)
  • Author(s): Kazumitsu Sugiura
  • Organizer: 12th Meeting of the German-Japanese Society of Dermatology
  • Place of Presentation: 東京都文京区(東京医科歯科大学)
  • Int'l Joint Research / Invited
• [Presentation] 膿疱症とDITRA(deficiency of interleukin-36 receptor antagonist) (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第32回日本臨床皮膚科医会 東海北陸ブロック総会
  • Place of Presentation: 名古屋市(キャッスルプラザ)
  • Invited
• [Presentation] IL36RN 遺伝子と膿疱性乾癬 (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第46回日本皮膚アレルギー・接触皮膚炎学会総会学術大会
  • Place of Presentation: 東京都新宿(京王プラザホテル)
  • Invited
• [Presentation] 稀でない遺伝性皮膚疾患 (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第203回愛知県皮膚科医会例会
  • Place of Presentation: 名古屋市(中日パレスクラウンホール)
  • Invited
• [Presentation] Genetic background of generalized pustular psoriasis (2016)
  • Author(s): Kazumitsu Sugiura
  • Organizer: 日本研究皮膚科学会第41回年次学術大会・総会
  • Place of Presentation: 仙台市(仙台国際センター)
  • Invited