Inflammatory cell death during acute-on-chronic kidney injury

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17290
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Jichi Medical University
• Principal Investigator: Komada Takanori 自治医科大学, 医学部, 講師 (90824730)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 慢性腎臓病 / 急性腎障害 / マクロファージ / パイロトーシス

Outline of Final Research Achievements

Cell death is a physiologically functional process that regulates signals to the surrounding cells. During CKD, the overriding insults can cause cell death of intrinsic kidney cells and immune cells and contribute to worse kidney outcomes. Inflammasomes are multi-protein complexes which regulate innate immune response and cell death called pyroptosis. We examined immune cell death in AKI and acute-on-chronic injury kidneys. Inflammasome formation and pyroptotic cell death in macrophages developed in the injured kidneys. We showed that a possible danger-associated molecular pattern (DAMP), double-stranded DNA, induced pyroptosis in kidney macrophages in the Aim2-dependent manner. We further demonstrated that many types of macrophages engaged in DNA-induced pyroptosis without releasing inflammasome-dependent cytokines. The differentiation status of dead macrophages seemingly determines the propagation of inflammation and contributes to the outcomes of acute-on-chronic kidney injury.

Free Research Field

腎臓病学

Academic Significance and Societal Importance of the Research Achievements

CKD腎という病的腎において、炎症細胞死の役割は未だ不明な点が多い。インフラマソームを介した炎症細胞死を制御することで、CKDの治療・進展予防に役立つ可能性がある。
本研究の成果により、二本鎖DNAが様々なマクロファージでパイロトーシスを誘導する可能性が示唆された。AKIおよびCKDは心血管病など様々な疾患の危険因子であり、有効な治療法が期待されている。CKD腎の炎症細胞死の重要性を示した本研究により、CKDのさらなる病態解明に向けて学術的・社会的な意義があると考えられる。