Research Focus
Immune cells release cellular ATP that fuels inside-out signaling mechanisms that regulate the activation and functions of neutrophils and T lymphocytes. Under normal circumstances, the released ATP regulates chemotaxis and proliferation of immune cells through autocrine feedback mechanisms that involve ATP and adenosine receptors. These purinergic signaling mechanisms regulate calcium influx and other downstream signaling pathways that are required for proper function of neutrophils and T lymphocytes. However, severe injuries, burns, and infections can cause the release of ATP from inflamed and damaged tissues. This systemic ATP interferes with the autocrine purinergic signaling mechanisms that regulate immune cell responses. This results in immune dysfunction that causes clinical complications such as multiple organ failure, immunosuppression, and sepsis. The focus of this laboratory has been to define the cellular and molecular mechanisms that lead to these complications.
Our work has revealed a complex network of metabolic pathways that regulate ATP release and the purinergic signaling mechanisms that control immune cell functions. This network involves mitochondria that produce the ATP that fuels purinergic signaling. Thus, mitochondria are the link between the metabolic and calcium signaling events and the purinergic signaling mechanisms that regulate immune cell functions. We found that mitochondrial function in T cells is reduced in critical care patients and that impaired mitochondrial ATP production is directly correlated with the severity of sepsis. Our studies suggest that pharmacological targeting of purinergic signaling is a promising new approach to restore immune competence in critical care and trauma patients.