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Enhancing Nix-dependent mitophagy relieves AKI by restricting TREM-1-mediated hyperactivation of inflammasome in

Pan Pan1, Jie Chen2, Fei Xie1

  • 1College of Pulmonary and Critical Care Medicine, 8th Medical Center, Chinese PLA General Hospital, Beijing, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|October 16, 2023
PubMed

Insights

Platelet mitophagy restricts inflammasome activation, protecting against sepsis-induced acute kidney injury (AKI). Targeting TREM-1 and BNIP3L in platelets offers a novel therapeutic strategy for septic AKI.

Area of Science:

  • Immunology
  • Pathology
  • Renal Medicine

Background:

  • Platelets play a crucial role in inflammation and organ injury.
  • Mitophagy in platelets may mitigate inflammasome overactivation and reduce acute kidney injury (AKI).

Purpose of the Study:

  • To investigate the role of Triggering receptor expressed on myeloid cells (TREM-1) and mitophagy in platelet-mediated septic AKI.
  • To explore the therapeutic potential of targeting platelet TREM-1 and mitophagy pathways.

Main Methods:

  • Established cecal ligation puncture (CLP)/LPS-induced AKI and TREM-1 knockout mice models.
  • Included septic patients with AKI for analysis.
  • Performed platelet transfer assays and evaluated mitophagy and inflammasome activation.

Main Results:

  • Increased TREM-1 expression and inflammasome hyperactivation were observed in platelets from CLP mice and septic patients.
  • TREM-1 deletion significantly reduced AKI and inflammasome hyperactivation.
  • Ablation of mitophagy receptor BNIP3L/Nix led to damaged mitochondria accumulation and platelet inflammasome hyperactivation.

Conclusions:

  • TREM-1 activates platelet inflammasomes, contributing to sepsis-related AKI.
  • Dysfunctional mitophagy and platelet inflammasome activation form an amplification loop driving AKI.
  • Targeting platelet TREM-1 and NLRP3/BNIP3L presents a potential therapeutic approach for septic AKI.
Keywords:
BNIP3L/NixNLRP3 inflammasomeTREM-1autophagymitochondrionplatelet

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