HMN 2026: How Diabetes flips immune cells from repair to inflammation in peripheral artery disease

Type 2 diabetes can turn immune cells that help with tissue repair and anti-inflammatory responses into triggers of chronic inflammation. A recent study investigated why people with type 2 diabetes are at a higher risk of severe complications from peripheral artery disease (PAD).

PAD is a common circulatory condition in which plaque buildup narrows the arteries, reducing blood flow, usually in the legs. This can lead to lower extremity infections and the formation of non-healing ulcers in people with diabetes.

Using RNA-sequencing and gene mapping, researchers discovered that diabetes causes certain immune cells called macrophages that express the protein TREM2 to reprogram their behavior from helping cells repair to causing harmful inflammation and preventing blood vessels from healing. The findings were published in Science Translational Medicine.

Intercepting the cross-talk

Diabetes has become a global health concern, with over half a billion people navigating life with a chronic metabolic condition. As lifestyles shift from active to more sedentary, the number of people living with diabetes is only expected to rise in the years ahead.

Diabetes raises the risk of developing other health conditions, including PAD, which restricts blood flow to the limbs and can lead to serious complications like amputations.

While these complications have been well established for quite some time, there still lacks effective treatments that can cure or even prevent them. A key challenge may lie in our limited understanding of how diabetes disrupts blood vessel function at the molecular level. While researchers have long suspected that endothelial cells and macrophages are major players, solid evidence has been lacking.

In this study, the researchers decided to intercept cell-to-cell communication within the blood vessels to make sense of how diabetes changes it, particularly the interactions between endothelial cells (ECs) and macrophages (MPs).

To do so, they studied human arteries from donors with and without type 2 diabetes. They used single-cell RNA sequencing to zoom in on individual cell types and identify which genes were switched on or off in each. To pinpoint exactly where this activity occurred, they turned to spatial transcriptomics, which helped them create a map of genetic activity within cells of the arterial structure.

In arteries from donors with type 2 diabetes, MPs and ECs exhibit elevated expression of the TREM2 receptor. The genetic testing revealed a two-way signaling loop between ECs and MPs, in which both cell types continuously activate one another. This sustained cross-talk promoted the transition of TREM2+ macrophages, a subpopulation of the immune cells, from a protective, anti-inflammatory state to proinflammatory foam-like cells, thereby increasing inflammation.

As these MPs shifted, they began to influence ECs, changing their behavior and prompting them to release chemicals that make blood vessel walls more sticky, which not only draws inflammatory cells into the vessels but also hinders healing.

The team tested human ischemic muscles—restricted blood supply—and found elevated levels of sTREM2, a soluble form of the signaling protein, suggesting its potential as a biomarker for identifying individuals at risk of PAD complications.

The researchers note that when TREM2 was blocked in cell and mouse models, inflammation eased, endothelial cells repaired more effectively, and blood flow bounced back after ischemic injury. If similar responses are observed in human muscle tissue, targeting TREM2 signaling could offer new treatment approaches for diabetic PAD, with the potential to improve preservation of affected limbs and support better recovery.

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