This career development award will establish Dr. Simmie Foster as a clinician-scientist specializing in thermoregulation of immunity in the context of depression. Dr. Foster has significant basic science expertise in inflammation and neuroimmunity, especially in mouse models, and now wishes to move towards becoming a patient-oriented researcher, studying human subjects and tissues. To accomplish this goal, she has identified several training objectives: 1) Develop expertise in the methodology to conduct patient-oriented research, including novel study design and advanced statistical analyses; 2) Further training in clinical and research mechanisms and applications of hyperthermia; 3) Training in collection, processing, and interpretation of immune and physiological biomarkers in human subjects critical to understanding the mechanisms of action of hyperthermia; and 4) Further training in the responsible conduct of randomized controlled trials. She has assembled an expert team to guide her in clinical trial design, hyperthermia sensing and treatment, and phenotyping of human tissues. Rationale: A hallmark of the systemic inflammatory response to infection or injury is fever. Yet the molecular links between thermoregulation and immunity remain unclear. Elevating the body temperature to fever range, even in the absence of overt immune stimuli, has been shown to ameliorate multiple ailments, especially those with an inflammatory basis, including psychiatric disease such as major depressive disorder (MDD). In this proposal, Dr. Foster plans a multi-level approach to investigate how heat-sensing by immune cells contributes to the inflammatory profile observed after exposure to hyperthermia, and specifically the consequences of elevated temperature on inflammasome activation. A candidate target for feedback regulation is IL-1, the prototypical proinflammatory cytokine and endogenous pyrogen (fever-inducer). The Woolf lab and others have shown that thermo-sensitive neurons interact with immune cells to regulate inflammation, indicating that heat sensing could play a role in inhibition of IL-1, and thus contribute to the beneficial effect of hyperthermia on inflammatory disease. In Aim 1, she tests the prediction that whole body hyperthermia induces an anti-inflammatory response characterized by induction of heat shock proteins and inhibition of inflammasome mediated IL-1 in patients with major depressive disorder. In Aim 2, using peripheral blood monocytes from healthy subjects, she dissects mechanisms by which exposure to elevated temperature inhibits the inflammasome; testing the hypothesis that macrophage sensing of elevated temperature through neuronal sensors inhibits production and processing of IL-1. In Aim 3, using immune cell neuronal co-cultures, she determines contribution of neuronal heat sensing to changes in inflammatory mediators produced by immune cells. The results of this study will lead to a more complete picture of how hyperthermi...