A Novel M2 Lipogenic Macrophages Associated with Fracture Callus Are Altered in Type 2 Diabetes
Abstract
Impaired wound healing represents a major complication associated with type 2 diabetes. US military Veterans (1 in 5) are affected by type 2 diabetes. Studies of wound repair in diabetic patients suggest that healing is delayed or suppressed due to changes in the population of inflammatory cells necessary for this process. However, little is known about the etiology of this low-level chronic inflammation. One of the principal cell populations in the immune system are white-blood cells derived from the bone marrow or spleen called macrophages, which engulf foreign substances. These macrophages are divided in two main populations, namely, macrophages type 1 (M1) and macrophages type 2 (M2). M1 macrophages are involved with killing of foreign mostly infectious substances, and M2 macrophages are involved with repairing and healing of damaged tissues. In recent studies, a potentially new population of macrophages has been identified that are specific for each human tissue and reside within them. These macrophages are thought to provide instrumental support in growth, repair, and maintenance of their respective tissues. These tissue resident macrophages have been classified as the M2 subtype. Recent studies in our laboratory looking at tissue regeneration after traumatic bone injury have found a unique macrophage population that rapidly expands at the site of injury. Further analysis of this novel population of macrophages suggests that they may be regulated similarly to adipose. We determined that these adipose-like macrophages present at the injury site are the M2 type. Studies in diabetes have found that in many tissues there is a significant increase in M1 macrophages within the tissues, suggesting that either they are replacing the normal tissue resident populations or that there are changes in the cells leading to their conversion to an M1 macrophage. M1 macrophages have been shown to be unable to support tissue regeneration, and their presence in tissue has been correlated with delayed wound repair. Recent studies suggest that TNFalpha secreted by M1 macrophages appears to hinder replication and expansion of essential bone stem cells, contributing to the delayed healing. Our own preliminary data shows that these macrophages are reduced in number within the fracture site in mouse with type 2 diabetes and have delayed fracture repair. Therefore, the focus of our studies is to characterize the unique macrophages identified during traumatic bone injury and to evaluate if they are functionally changed during diabetes rendering them unable to support wound healing. Therefore, in addressing the PRMRP Topic Area of diabetes and tissue regeneration and wound repair, we propose to demonstrate that novel M2-like macrophages that are essential to tissue repair are compromised either in their ability to expand or their function. We will look at these cells in two different models of type 2 diabetes. In this way, we will show how changes in macrophages may result in the complication of delayed or suppressed wound healing associated with type 2 diabetes. Our goal for this project would be to develop a therapy that will either replace the macrophages if they fail to expand or will allow them to retain their M2-like state. We propose to test these therapeutic approaches in the current studies. In addition, M2 macrophages have been shown to have unique metabolism that is required for these cells to be functional. Unfortunately, these metabolic pathways are the same pathways used by liver cells, which are the target for most all drugs prescribed to treat type 2 diabetes. While these drugs have been thought to be somewhat specific for the liver, no one has established if they also could be playing a role in the increase in M1 macrophages at the expense of M2. If these drugs also drive this process, then while beneficial to prevent or reduce adverse effects of elevated blood glucose they also may contribute to impaired wound repair. In t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110285
Entities
People
- Elizabeth Olmstead-davis
Organizations
- Houston Methodist Research Institute
- United States Army