Re-directing the STING Pathway in Diabetic Wounds Could Accelerate Healing

The body’s movement of nutrients obtained from food is calculated wisely. Our cells are blessed to be able to use and drag them without any help most of the time. However, there are instances when the cells need a boost from an external friend to do such a job. 

One example is the energy nutrient glucose. Our cells are incapable to absorb glucose from the blood without the help of insulin. Hence naturally, the loss of insulin will cause a significant danger in the bloodstream; by raising the glucose level to an abnormal range. 

Since the pancreas is a giant factory for insulin, pancreatic damage will affect insulin production. Diabetes is an example of such damage. According to the World Health Organization, diabetes has steadily increased during the past few decades, which is a loud alarm! 

Diabetes can be of two types: Type 1- the person here is entirely deficient in insulin production as it is an autoimmune disease where a body’s antibodies are attacking the body’s insulin-producing beta cells in the pancreas; and Type 2- when there is some defect in insulin secretion, meaning there isn’t enough insulin in the bloodstream.

Diabetes is considered a chronic disease without a cure. It can also lead to more long-lasting diseases like kidney failure or blindness. It can also raise problems in delaying wound healing, which is known as a diabetic wound (DW). Years of research have pointed fingers towards the excessive presence of pro-inflammatory M1 macrophages, as the major reason behind the healing impairment. Unfortunately, in worse scenarios, those wounds lead to amputation. 

Usually, wound healing goes through three significant steps:

1- Inflammation – where the immune cells release cytokines to call in other immune cells and fight infection/foreign agents altogether. 

2- Proliferation – where the cells around the wound start to re-boost, and the new blood vessels form (angiogenesis). 

3- Remodeling – where the scar forms and the wound is closed. 

Nevertheless, in a diabetic person, almost all these steps are altered due to excessive stress on the body. As a result, the healing process stays longer in the inflammation step where M1 macrophages constantly release pro-inflammatory cytokines like IL-1beta. 

In recent studies, scientists showed that under certain conditions, the presence of cytoplasmic DNA (and not only pathogenic DNA) could easily trigger the stimulator of the interferon gene (STING). Thus, STING-associated pathways could be responsible for pathological auto-inflammatory responses and play a massive role in the pancreas or liver diseases (metabolic diseases) as well as some autoimmune diseases. 

Perhaps DW is another such auto-inflammatory condition controlled by the cGAS-STING pathway. To answer that, a group from Macau University in China recently investigated if STING is involved in cellular dysfunction in DW.

For their experiment, the group used mouse models and cooperated skin biopsies from non-diabetic wounds and diabetic patients to study the expression of some inflammatory proteins. 

The group proved that the expression of inflammatory proteins such as IL-1beta and pro-inflammatory macrophages are much higher in DW tissues from human patients. Surprisingly, intermediate proteins from the cGAS-STING pathway were over-expressed in those wounded tissues, especially on macrophages. Overall, the results showed that STING and its downstream activated proteins co-localized on macrophages and were essential in wound progression. 

When comparing mouse models, they again detected that the diabetic environment enhances STING activation on wounded tissue, which inhibits healing and worsens the injury. Inhibiting STING in mice reduced the number of macrophages in the wound tissue and improved healing.

The next question asked was: does high glucose level stimulate STING? Yes, it does. The reason is that when the glucose level is high, it will increase and build up reactive oxygen species (ROS) in the mitochondria. As a result, the mitochondrial DNA leaks out and triggers the DNA sensor – STING – in macrophages, causing more inflammation. The group also noticed that STING activation in wound tissues of diabetic mice not only polarized macrophages into pro-inflammatory macrophages (while reducing the anti-inflammatory M2 macrophage population), but it also damaged the growth and migratory capabilities of vascular endothelial cells of the blood vessels. 

After seeing how important the STING pathway is in DW, the group raised a cell therapy proposal! They aimed to re-direct the macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 cells via STING gene editing in macrophages. They tested their proposal on mice by injecting STING-edited M2 cells into the DW. The results were terrific! The presence of M2 decreased the expression of pro-inflammatory IL- 1beta in the wound. It also remarkably increased the number of new vessels and promoted the accumulation of collagen fibers on the wound surface to accelerate the healing. Moreover, the treatment infiltrated more M2 phenotype into the wound and inhibited further STING activation in diabetic wound mice. 

Undoubtedly, the human body is a lot more complicated than a mouse, and having it under diabetic stress will exhaust it at a point. Therefore, this promising proposal may potentially take a load off the immune system’s shoulders, until we can cure or prevent the actual disease. 

Source:

• Geng K, Ma X, Jiang Z, Huang W, Gu J, Wang P, Luo L, Xu Y, Xu Y. High glucose-induced STING activation inhibits diabetic wound healing through promoting M1 polarization of macrophages. Cell Death Discov. 2023 Apr 26;9(1):136. doi: 10.1038/s41420-023-01425
• Dasari N, Jiang A, Skochdopole A, Chung J, Reece EM, Vorstenbosch J, Winocour S. Updates in Diabetic Wound Healing, Inflammation, and Scarring. Semin Plast Surg. 2021 Aug;35(3):153-158. doi: 10.1055/s-0041-1731460.

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