Pathogenesis of sepsis-induced dysfunction of innate immunity

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Our long-term goal is to study molecular mechanisms underlying pathogenesis of sepsis, a potentially life-threatening illness caused by severe traumatic injury and trauma infections. Sepsis is the most costly condition for VA hospitals to treat. When sepsis becomes severe, it has a high mortality rate even with appropriate care. Sepsis is associated with overwhelming inflammatory response and dysregulation of innate immunity, which can lead to persistent inflammation and multiple organ failure. The mechanisms by which this pathophysiological problem occurs remain unknown. Evidence shows that macrophages play an important role in the innate immune response. They undergo polarization to M1 phenotype (i.e. inflammatory macrophages) and M2 phenotype (i.e. anti-inflammatory macrophages) in inflammation depending on local environments. Currently, the exact phenotype of macrophages in inflammatory sites during sepsis is not clear. The molecular mechanisms underlying polarization of macrophages in sepsis is unknown. Furthermore, the impact of macrophage polarization in pathogenesis of sepsis-associated immune dysregulation and tissue injury has not been elucidated. Thus, we will focus on filling these knowledge gaps in this project. In preliminary studies, we found that polymicrobial sepsis is associated with increase in M1-like macrophages in mouse lungs. M1 macrophage activation is coupled with increase in levels of Sirt6, a key regulator for cell metabolism. Furthermore, loss-of-function and gain-of-function studies revealed the link between Sirt6 and M1 macrophage activation. Therefore, we will study whether Sirt6 plays an important role in septic insult-induced M1 macrophage activation and tissue injury, and if so, we will study the molecular mechanism by which Sirt6 promotes M1 macrophage activation. To this end, we will execute the following studies. Specific Aim 1 will determine the role of Sirt6 in M1 macrophage activation under cytokine-stimulation and septic condition. Specific Aim 2 will study how Sirt6 potentiates M1 macrophage activation in inflammation. Specific Aim 3 will examine whether Sirt6-associated signal axis in macrophages impacts pathogenesis of sepsis. Achievement of these specific aims will provide novel information regarding how severe inflammation in sepsis causes imbalance of M1-M2 macrophage activation, which may ultimately lead to development of strategies for maintaining macrophage homeostasis in patients with sepsis. Data derived from the proposed work will expand our knowledge on mechanisms underlying progression of sepsis to persistent inflammation and multiple organ injury. Sepsis is a common and serious complication for surgery patients in the Department of Veterans Affairs Healthcare System. Thus, the subject matter of this proposal is timely important and links to clinical application for management of VA patients with critical illness.