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

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.

• Authors: Shu Li, He Xu, Mingqing Song, Brian I Shaw, Qi-Jing Li, Allan D Kirk
• Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (Am J Transplant) Vol. 22 Issue 6 Pg. 1578-1592 (06 2022) ISSN: 1600-6143 [Electronic] United States
• PMID: 35322536 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.

Chemical References

• NF-kappa B
• Nuclear Proteins
• Phosphoproteins
• IFI16 protein, human

Topics

• Animals
• Endothelial Cells (metabolism)
• Heart Transplantation (adverse effects)
• Humans
• Mice
• Mitochondria (metabolism)
• NF-kappa B (metabolism)
• Nuclear Proteins (genetics, metabolism)
• Phosphoproteins
• Tissue Donors