Pathological analysis of skin fibrosis, focused on type 2 innate immune lymphoid cells

• Project/Area Number: 24659520
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Chiba University
• Principal Investigator: KAMBE Naotomo 千葉大学, 医学研究院, 准教授 (50335254)
• Co-Investigator(Kenkyū-buntansha): NAKAE Susumu 東京大学, 医科 学研究所, 准教授 (60450409)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2012: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 皮膚炎症・再生学 / 皮膚硬化性病変 / ＩＬ-33

Research Abstract

We have studied the mechanism of cryopyrin-associated periodicsyndrome (CAPS), in which an active mutant of NLRP3 spontaneously forms inflammasome andinduces hyper-production of IL-1β. This study led us to focus on the pivotal role of IL-1 in skindiseases. Recently, people pay attention to another IL-1 family molecule, IL-33, because IL-33released from damaged cells in inflammation is critically involved in inflammatory response by aproduction of Th2 cytokines and a degranulation of mast cells. In addition, IL-33 induces a largeamount of Th2 cytokine production from innate lymphoid cells (ILCs). ILCs are newly identifiedlymphoid lineage cells, keep haematopoietic stem cell markers and are present in the mesentericfat-associated lymphoid clusters.
Interestingly, the structure of mesenteric fat-associated lymphoid clusters shares thesimilar feature with that of aggregated clusters of lymphoid cells in subcutaneous fat in localizedscleroderma. Also serum IL-33 is reported to be elevated in scleroderma and serum levels of IL-33is well correlated with the severity of cutaneous sclerosis in scleroderma. Therefore, we studied therole of IL-33 in bleomycin-induced scleroderma murine model by comparing the effect in IL-33deficient mice and wild type mice.
Six weeks after bleomycin-treatment, we obtained localized cutaneous sclerosisaccompanied with increased skin fibrosis in wild type mice. However, lymphoid cell infiltrationwas not observed in the skin lesion. Unfortunately, the cutaneous sclerosis including histologicalfeatures in IL-33 deficient mice was almost identical to that in wild type mice. We concluded from these results that we should verify the cutaneous role of IL-33 by focusing on Th2 immuneresponse, and now we are establishing such a model to confirm it.

Research Products

• [Journal Article] Dok adaptors play anti-inflammatory roles in pulmonary homeostasis. (2013)
  • Author(s): Mashima R, Arimura S, Kajikawa S, Oda H, Nakae S, Yamanashi Y.
  • Journal Title: Genes to Cells Volume: 18 Issue: 1 Pages: 56-65
  • DOI: 10.1111/gtc.12016
  • Peer Reviewed
• [Journal Article] Role of Interleukin-33 in Innate-Type Immune Cells in Allergy (2013)
  • Author(s): Nakae S, Morita H, Ohno T, Arae K, Matsumoto K, Saito H
  • Journal Title: Allergology International Volume: 62 Issue: 1 Pages: 13-20
  • DOI: 10.2332/allergolint.13-RAI-0538
  • NAID: 130004477181
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed
• [Journal Article] ST2 Requires Th2-, but Not Th17-, Type Airway Inflammation in Epicutaneously Antigen-Sensitized Mice (2012)
  • Author(s): Morita H, Arae K, Ohno T, Kajiwara N, Oboki, K, Matsuda A, Suto H, Okumura K, Sudo K, Takahashi T, Matsumoto K, Nakae, S
  • Journal Title: Allergology International Volume: 61 Issue: 2 Pages: 265-273
  • DOI: 10.2332/allergolint.11-OA-0379
  • NAID: 130004477129
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed
• [Journal Article] Epithelial cell-derived IL-25, but not Th17 cell-derived IL-17 or IL-17F, is crucial for murine asthma (2012)
  • Author(s): Suzukawa M, Morita H, Nambu A, Arae K, Shimura E, Shibui A, Yamaguchi S, Suzukawa K, Nakanishi W, Oboki K, Kajiwara N Ohno T, Ishii A, Korner H, Cua DJ, Suto H, Yoshimoto T, Iwakura Y, Yamasoba T, Ohta K, Sudo K, Saito H, Okumura K, Broide DH, Matsumoto K, Nakae S
  • Journal Title: J Immunol Volume: 189 Pages: 3641-52
  • Peer Reviewed
• [Journal Article] Interleukin-33 in allergy. (2012)
  • Author(s): Ohno T, Morita H, Arae K, Matsumoto K, Nakae S.
  • Journal Title: Allergy. Volume: 67 Issue: 10 Pages: 1203-14
  • DOI: 10.1111/all.12004
  • Peer Reviewed
• [Journal Article] 「皮膚免疫学-免疫臓器としての意義と病態」皮膚と自己炎症性機序による肉芽腫性疾患 (2012)
  • Author(s): 中野倫代,神戸直智
  • Journal Title: 医学のあゆみ Volume: 242 Pages: 791-4
• [Journal Article] NLRP3インフラマソームを介したマスト細胞の活性化 (2012)
  • Author(s): 神戸直智,中村悠美
  • Journal Title: 臨床免疫・アレルギー科 Volume: 58 Pages: 560-4
• [Journal Article] IL-33と慢性アレルギー炎症 (2012)
  • Author(s): 大野建州,東みゆき,中江進
  • Journal Title: 実験医学 Volume: 30 Pages: 918-5
• [Journal Article] IL-33によるマスト細胞の活性化 (2012)
  • Author(s): 新江賢,大野建州,森田英明,松本健治,中江進
  • Journal Title: 臨床免疫・アレルギー科 Volume: 57 Pages: 625-3
• [Journal Article] IL-33によるマスト細胞・好塩基球の活性化とアレルギー疾患 (2012)
  • Author(s): 森田英明,新江賢,大野建州,松本健治,中江進
  • Journal Title: 炎症と免疫 Volume: 20 Pages: 340-50
• [Journal Article] IL-33とアレルギー (2012)
  • Author(s): 大野建州,森田英明,新江賢,松本健治,中江進
  • Journal Title: IgE practice in asthma Volume: 6 Pages: 11-17
  • NAID: 40022317104
• [Journal Article] IL-33による慢性アレルギー炎症 (2012)
  • Author(s): 大野建州,森田英明,新江賢,松本健治,中江進
  • Journal Title: アレルギーの臨床 Volume: 32 Pages: 918-23
• [Journal Article] IL-25,IL-33と自然リンパ球～感染防御,アレルギー疾患へのかかわり～ (2012)
  • Author(s): 大野建州,東みゆき,中江進
  • Journal Title: 実験医学 Volume: 30 Pages: 3062-71
• [Journal Article] Epithelial cell-derived IL-25, but not Th17 cell-derived IL-17 or IL-17F, is crucial for murine asthma. (2012)
  • Author(s): Suzukawa M, Morita H, Nambu A, 他22名, Nakae S.
  • Journal Title: J Immunol. Volume: 189 Pages: 3641-52
  • Peer Reviewed
• [Journal Article] 「皮膚免疫学－免疫臓器としての意義と病態」皮膚と自己炎症性機序による肉芽腫性疾患. (2012)
  • Author(s): 中野倫代，神戸直智.
  • Journal Title: 医学のあゆみ. Volume: 242 Pages: 791-4
• [Journal Article] NLRP3インフラマソームを介したマスト細胞の活性化. (2012)
  • Author(s): 神戸直智，中村悠美.
  • Journal Title: 臨床免疫・アレルギー科. Volume: 58 Pages: 560-4
• [Journal Article] IL-33と慢性アレルギー炎症. (2012)
  • Author(s): 大野建州，東みゆき，中江 進.
  • Journal Title: 実験医学. Volume: 30 Pages: 918-5
• [Journal Article] IL-33によるマスト細胞の活性化. (2012)
  • Author(s): 新江 賢，大野建州，森田英明，松本健治，中江 進.
  • Journal Title: 臨床免疫・アレルギー科. Volume: 57 Pages: 625-3
• [Journal Article] IL-33によるマスト細胞・好塩基球の活性化とアレルギー疾患. (2012)
  • Author(s): 森田英明，新江賢，大野建州，松本健治，中江 進.
  • Journal Title: 炎症と免疫 Volume: 20 Pages: 340-50
• [Journal Article] IL-33とアレルギー. (2012)
  • Author(s): 大野建州，森田英明，新江賢，松本健治，中江 進
  • Journal Title: IgE practice in asthma. Volume: 6 Pages: 11-17
  • NAID: 40022317104
• [Journal Article] IL-33による慢性アレルギー炎症. (2012)
  • Author(s): 大野建州，森田英明，新江賢，松本健治，中江 進.
  • Journal Title: アレルギーの臨床. Volume: 32 Pages: 918-23
• [Journal Article] IL-25，IL-33と自然リンパ球〜感染防御，アレルギー疾患へのかかわり〜. (2012)
  • Author(s): 大野建州，東みゆき，中江 進.
  • Journal Title: 実験医学 Volume: 30 Pages: 3062-71