TREM2 signaling impairs ischemic vascular repair in diabetes

What the study found: Diabetes-related TREM2 (triggering receptor expressed on myeloid cells 2) signaling between mononuclear phagocytes and endothelial cells was identified as a driver of diabetic vascular dysfunction, and it was linked to impaired ischemic vascular repair. The study also found elevated endothelial-cell TREM2 signaling in human peripheral arterial disease, especially when diabetes was present.
Why the authors say this matters: The authors conclude that their findings highlight TREM2-endothelial cell interaction as a potential therapeutic target in diabetes-associated peripheral arterial disease, which is peripheral arterial disease caused or worsened by diabetes.
What the researchers tested: The researchers used single-cell RNA sequencing and spatial transcriptomics to profile human mesenteric arteries from non-diabetic donors and donors with type 2 diabetes. They also tested TREM2 inhibition and activation in cell experiments and in diabetic mouse models with hindlimb ischemia, a model of peripheral arterial disease.
What worked and what didn't: TREM2-positive mononuclear phagocytes showed foam cell-like features and a proinflammatory gene profile in diabetes. In vitro, TREM2 inhibition reduced proinflammatory responses in mononuclear phagocytes and endothelial cells and increased endothelial migration, while in diabetic mice with hindlimb ischemia, TREM2 blockade improved perfusion recovery and TREM2 activation worsened ischemic injury.
What to keep in mind: The abstract does not describe detailed limitations beyond the study’s use of specific human vessel samples, cell experiments, and diabetic mouse models.

Key points

• Single-cell and spatial profiling of human arteries identified TREM2 as a top diabetes-induced gene in mononuclear phagocytes.
• Endothelial cells showed increased TREM2 ligands in diabetes, suggesting stronger TREM2-endothelial cell signaling.
• TREM2-positive mononuclear phagocytes had foam cell-like features and a proinflammatory profile in diabetes.
• Blocking TREM2 reduced inflammatory responses and improved endothelial migration in vitro.
• In diabetic mice with hindlimb ischemia, TREM2 blockade improved perfusion recovery, while TREM2 activation worsened injury.