IFI16-STING-NF-κB signaling controls exogenous mitochondrion-induced endothelial activation

Shu Li, He Xu*, Mingqing Song, Brian I. Shaw, Qi Jing Li, Allan D. Kirk

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Mitochondria released from injured cells activate endothelial cells (ECs), fostering inflammatory processes, including allograft rejection. The stimulator of interferon genes (STING) senses endogenous mitochondrial DNA, triggering innate immune activation via NF-κB signaling. Here, we show that exogenous mitochondria exposure induces EC STING-NF-κB activation, promoting EC/effector memory T cell adhesion, which is abrogated by NF-κB and STING inhibitors. STING activation in mitochondrion-activated ECs is independent of canonical cGMP-AMP synthetase sensing/signaling, but rather is mediated by interferon gamma-inducible factor 16 (IFI16) and can be inhibited by IFI16 inhibition. Internalized mitochondria undergo mitofusion and STING-dependent mitophagy, leading to selective sequestration of internalized mitochondria. The exposure of donor hearts to exogenous mitochondria activates murine heart ECs in vivo. Collectively, our results suggest that IFI16-STING-NF-κB signaling regulates exogenous mitochondrion-induced EC activation and mitophagy, and exogenous mitochondria foster T cell–mediated CoBRR. These data suggest a novel, donor-directed, therapeutic approach toward mitigating perioperative allograft immunogenicity.

Original languageEnglish
Pages (from-to)1578-1592
Number of pages15
JournalAmerican Journal of Transplantation
Volume22
Issue number6
DOIs
StatePublished - Jun 2022
Externally publishedYes

Keywords

  • NF-κB
  • endothelial cells
  • interferon gamma-inducible factor 16
  • mitochondria
  • stimulator of interferon genes

Fingerprint

Dive into the research topics of 'IFI16-STING-NF-κB signaling controls exogenous mitochondrion-induced endothelial activation'. Together they form a unique fingerprint.

Cite this