Sepsis mouse model using TLR agonists: focuses on TLR7/8 and TLR9 ligands, immune tolerance state, and effects on lipid metabolism

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K18336
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55060:Emergency medicine-related
• Research Institution: Teikyo University
• Principal Investigator: Seki Reiko 帝京大学, 医療技術学部, 講師 (30527495)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 炎症 / TLR / 敗血症 / 肝障害 / 脂質代謝 / トレランス

Outline of Final Research Achievements

To gain insights into the roles for neutrophils and platelets and the lipid metabolism in the liver, we used mice model in which a variety of TLR ligands causes systemic inflammation accompanied by liver injury. The following findings were obtained.
(1) Gr-1+ cells involving neutrophils have an anti-inflammatory and protective role in the systemic inflammation/liver dysfunction model. (2) CD36 gene expression is profoundly upregulated in the liver during the tolerance state during which the immune response is suppressed after the TLR ligand induced inflammation. (3) Acute stress causes upregulation of CD36 gene and a rapid initial decrease in serum triglyceride followed by a subsequent increase. (4) TLR agonists that induces liver dysfunction compromise the increase of the serum triglyceride after the initial decrease.
Taken together, these findings demonstrate a mechanism by which the lipid metabolism in the liver plays regulatory roles in inflammation and rapid immune response.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

私たちは、敗血症でみられる免疫応答が弱くなっているトレランス状態や肝不全により炎症が増強されている状態、さらには拘束といった身体的なストレスにおいても、マウス肝臓の脂肪酸の取り込みに関するCD36遺伝子発現が迅速に著しく亢進することを見いだした。また血清TGの大きな変動を見いだし、肝臓の脂質代謝が炎症初期から大きく関与することを明らかにした。一方、TLRアゴニストはその変化を抑制することから細菌感染による敗血症増悪の過程を解明するヒントをつかむことができた。