Elucidation of control mechanism of skin inflammatory diseases involving TLRs

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K16352
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Juntendo University
• Principal Investigator: Izawa Kumi 順天堂大学, 医学(系)研究科(研究院), 助教 (80708313)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: CD300 / TLR / LPS / ceramide

Outline of Final Research Achievements

A rapid accumulation of neutrophils with edema was observed in the ear skin of CD300f KO mice compared with WT mice 1 day after E. coli inoculation. However, skin inflammation, characterized by edema and neutrophil accumulation, subsided in the ear skin of CD300f KO mice 6 days after E. coli inoculation, presumably because E. coli was cleared by rapidly recruited neutrophils. We observed persistent inflammation after E. coli infection in the ear skin of WT mice and lower counts of E. coli were noted in the ears of CD300f KO mice 5 days after E. coli inoculation. Furthermore,we found that treatment with anti-ceramide Ab, but not with a control Ab, disrupted the ceramide-CD300f interaction and lowered the counts of E. coli in the inoculated ear skin of WT mice 5 days after E. coli inoculation at levels comparable to those of CD300f KO mice. Disrupting the ceramide-CD300f interaction promote the recruitment of neutrophils to sites of infection that efficiently engulf and kill E. coli.

Free Research Field

アレルギー

Academic Significance and Societal Importance of the Research Achievements

CD300f欠損マウスは盲腸結紮穿刺による敗血症性腹膜炎に対して抵抗性を示し、野生型マウスに対するセラミド抗体やCD300f-Fcの投与は敗血症性腹膜炎の致死率を改善させることが証明されている。今回、大腸菌の皮膚感染ではセラミドとCD300fの結合は好中球遊走因子の産生を抑制して好中球集積を抑えるため、感染防御には不利に働いた。また、セラミド抗体の投与は腹膜炎モデル同様に、皮膚における大腸菌の排除を改善させた。ヒトCD300fにおいても同様の結果が得られ、セラミドとCD300fの結合を阻害する薬剤はグラム陰性桿菌感染（皮膚及び全身）の治療薬として有効である可能性が示唆された。