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Abstract: TH-PO090

Double-Stranded DNA-Induced AIM2 Pyroptosis Limits Excessive Inflammation During Rhabdomyolysis-Induced AKI

Session Information

  • AKI: Mechanisms - I
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Baatarjav, Chintogtokh, Jichi Ika Daigaku, Shimotsuke, Tochigi, Japan
  • Komada, Takanori, Jichi Ika Daigaku, Shimotsuke, Tochigi, Japan
  • Takahashi, Masafumi, Jichi Ika Daigaku, Shimotsuke, Tochigi, Japan
Background

Rhabdomyolysis-induced acute kidney injury (RIAKI) is a severe complication of rhabdomyolysis, reportedly in part via double-stranded DNA (dsDNA) released from necrotic muscle. A dsDNA-sensor absent in melanoma 2 (AIM2) engages inflammasome activation, leading to maturation of IL-1β and gasdermin D (GSDMD)-dependent pro-inflammatory cell death called pyroptosis. The role of AIM2-mediated pyroptosis during RIAKI remains unknown.

Methods

C57BL/6J-background wild type (WT) and Aim2-knockout (Aim2-KO) mice underwent intramuscular glycerol injection to induce RIAKI. Isolated kidney macrophages and bone marrow-derived macrophages were subjected to dsDNA-induced pyroptosis assays in vitro.

Results

A specific endonuclease for dsDNA, DNase-I, effectively ameliorated tubular injury and inflammation during RIAKI, corroborating that dsDNA is a critical danger molecule of RIAKI. TUNEL staining and immunoblotting for GSDMD in RIAKI kidneys demonstrated massive macrophage pyroptosis in WT, and Aim2-KO diminished this response. While pyroptosis was suppressed, Aim2-KO kidneys displayed abnormally more macrophage accumulation than WT. Aim2-KO promoted RIAKI by TANK-binding kinase 1 (TBK1)-NF-κB signalling and recruited more CD206+CXCR3+ macrophages, resulting in excessive kidney inflammation, fibrosis, and sustained kidney dysfunction. In in vitro study, dsDNA induced swift pyroptotic cell death in kidney macrophages without releasing IL-1β. Aim2-KO macrophages were devoid of pyroptosis in response to dsDNA. These surviving Aim2-KO macrophages alternatively developed STING-TBK1-IRF3/NF-κB activation, and secreted IFNβ and TNFα. Conditioned medium of dsDNA-treated Aim2-KO macrophages, not WT macrophages, upregulated pro-inflammatory genes on macrophages and kidney tubular epithelial cells. These results indicate pro-inflammatory functions of Aim2-deficient macrophages escaped from pyroptosis.

Conclusion

Aim2 deficiency worsens inflammation and fibrosis of RIAKI despite reduced macrophage pyroptosis. Macrophage survivors lacking Aim2 potentiate inflammation on surrounding cells. dsDNA-induced, AIM2-dependent macrophage pyroptosis potentially provides a resolution of inflammation and determines the healing process of RIAKI.

Funding

  • Government Support – Non-U.S.