Project Summary:
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.