In early work, we investigated the impact of emergency granulopoiesis and the expansion of myeloid derived suppressor cells (MDSCs) following traumatic injury and inflammation. Findings from research using both preclinical and human models indicated that early generation – within hours to days of injury – and replenishment of adequate neutrophils and monocytes is necessary to survival. We were the first to show, using knockout models of sepsis, that this early innate immune response is critical.
We also found that over a longer duration, MDSCs can suppress the adaptive immunity of CD4+ and CD8+ cells, stimulate B cell antibody production and lead to ongoing catabolism. This led us to hypothesize that MDSCs play a role in the ongoing immune system dysfunction that leads to poor sepsis outcomes. Having established the key role of innate immunity, we next looked at the role adaptive immunity plays in sepsis survival. In that work, we were among the first to further clarify the (non-essential) role of T and T regulatory cells and the (essential) role of B cells.
Our work on granulopoesis and the role of MDSCs in innate and adaptive immunity led us to hypothesize that similarities in immune dysfunction associated with diabetes and obesity and in trauma and sepsis might be implicated in poor outcomes in these patient populations. We have begun to tease apart, cell-type by cell-type, the role and deficiencies of the innate and adaptive immune systems in preclinical and human models of diabetes and obesity to better understand the complex interplay among these conditions and trauma, inflammation, ongoing infection and sepsis.
Work using data from human trauma patients revealed distinct cytokine signatures of obese and of lean patients, with obese patients showing a muted cytokine response to injury and increased nosocomial infections, organ failure and subsequent onset of organ failure. We discovered that damage was propagated by two signaling molecules, TNF-alpha and CXCL12. We further showed in preclinical models that blocking these pathways helped preserve kidney function and prevent the organ injuries that lead to organ failure. Extending the work, we are looking at the functional immunological impact of bariatric surgery, which to date has proven the most effective treatment for obesity and can lead to long-term improvements in diabetes.
To these ends, we use preclinical models to replicate trauma and sepsis, and we are one of the few laboratories to combine them with preclinical models of obesity and type 2 diabetes. In experiments using these models, we saw a significant (three-fold) difference in survival between lean and obese mice with sepsis, and this led us to further investigate why the obese group wasn't able to clear the infection as effectively as the lean group.
In further experiments, we found that the neutrophils and monocytes in obese mice with diabetes are deficient in several ways, including their ability to engulf bacteria and generate reactive oxygen species to clear the infection. This research also found down-regulated AXL and MER receptor tyrosine kinase gene transcripts, which influence phagocytosis.
Next, we looked at the use of GM-CSF, which has been shown to improve lung injury outcomes in humans. We found that administration of GM-CSF improved survival by augmenting these two key cellular functions.