Role of pregnane x receptor activation on macrophage function and diabetic wound healing

The National Institute of Environmental Health Sciences (NIEHS) awarded a $439,500 project grant under the Environmental Health program (CFDA 93.113) to Mississippi State University (MSU) to investigate the impact of pregnane X receptor (PXR) activation on macrophage function and its effects on diabetic wound healing. The 3-year project aims to determine the role of PXR in macrophage polarization, phagocytic/bactericidal activity, and pressure-induced wound healing kinetics under normal and hyperglycemic conditions using wild-type and PXR knockout mouse models. Additionally, the project will evaluate the ability of PXR to augment the pathogenicity of Staphylococcus aureus isolates from diabetic foot ulcers. The research seeks to further elucidate the deleterious effects of PXR activation on wound healing, which could inform the identification of environmental xenobiotics as risk factors for non-healing diabetic foot ulcers.

Abstract

While there are a significant number of CO-morbidities associated with type 1 and type 2 diabetes (T1D and T2D), one of the more prevalent and severe sequalae of diabetes is diabetic foot ulceration (DFU) with approximately 25% of diabetics developing DFU in their lifetime. Out of all diabetics with DFU, approximately 15-20% of these cases will result in limb amputation due to incomplete healing. Under normal conditions, wound healing is a finely tuned, orchestrated effort by a host of cell types. Amongst these cell types, macrophage function, specifically macrophage plasticity, has been shown to play a critical role in normal wound healing. Thus, alterations in macrophage plasticity and/or function may have a detrimental effect on wound healing. Recent studies have shown that exposure to environmental contaminants, such as organochlorine pesticide metabolites and polychlorinated biphenyls among others, can alter macrophage function. However, the mechanisms governing environmental exposure and other xenobiotic related alterations in macrophage function remain elusive. One potential mechanism governing these exposures is activation of the pregnane x receptor (PXR). The PXR has been widely studied for its role in xenobiotic metabolism due to high levels of expression in the intestines and the liver as well as its ability to bind and become activated by a diverse set of ligands, including commonly used therapeutics and a wide array of environmental contaminants. Thus, the overall hypothesis of this application is that activation of the PXR decreases macrophage plasticity via decreased pro-inflammatory polarization with a corresponding decrease in bactericidal efficacy which will have a deleterious effect on pressure-induced wound healing. We will test this hypothesis in the following three specific aims. In aim 1, we will determine the role of the PXR in macrophage polarization and phagocytic/bactericidal activity in primary macrophages isolated from wild type and PXR knock out (KO) mice under normo- and hyperglycemic conditions. In aim 2 we will determine the effects of PXR activation on pressure-induced wound healing kinetics in both normal and streptozotocin (STZ)-induced diabetic wild type and PXR KO mice. Lastly in aim 3 we will evaluate the ability of the PXR to augment the pathogenicity of clinically relevant diabetic foot ulcer s. Aureus isolates. Successful completion of these studies will further delineate the role of the PXR in macrophage function as well as determine if augmentation of PXR function may be deleterious to healing of s. Aureus-infected pressure wounds, which is critical given increased s. Aureus colonization is positively associated with non-healing dfus. If PXR plays a deleterious role in wound healing, xenobiotics which activate PXR could be identified as a risk factor for non-healing dfus to tailor therapeutic regimens in a patient specific manner.