This research intends to discover mechanisms in hibernators that modulate immune responses in sterile sepsis. Sepsis is a systemic inflammatory response that can lead to severe organ damage. In only fifty percent of septic patients, sepsis is linked to an infectious organism. One of the causes for such 'sterile infection' is ischemia-reperfusion injury. Although sepsis is associated with high mortality rates, there is no FDA-approved drug for modulation of the immune response in sepsis. Hibernation might provide the answers for adequate immune modulation and prevention of organ damage. Hibernation consists of periods of lowered metabolism and body temperature (torpor), alternating with euthermic periods (arousals). Interestingly, several cycles of torpor and arousal nor ischemia-reperfusion lead to organ damage in hibernators. Reversible immune suppression is believed to constitute one of the organ protective mechanisms in hibernation. During torpor, levels of circulating leukocytes (mainly neutrophils and lymphocytes) drop by 90% and lymphocytes show reduced functionality. Sphingosine-1-phosphate (S1P) and the S1P receptor 1 (S1P1) have important roles in the regulation of lymphocyte function and are implicated in the lymphopenia found in hibernators during torpor. The experiments proposed in this research investigate the role of the innate (tissue resident macrophages) and adaptive (lymphocytes) immune system in hibernation, specifically focusing on the role of S1P and S1P1, and their applicability in a model of sterile sepsis. Research question: What are the underlying mechanisms in hibernators that modulate the innate as well as the adaptive immune responses, and how can we exploit these mechanisms in sterile sepsis? We propose 5 aims to investigate the research question:
1. Establish the role of sphingosine-1-phosphate, sphingosine kinase-1 and ATP-binding cassette C1 transporter in the regulation of lymphocyte proliferation.
2. Determine the role of S1P1 in lymphocyte recirculation in hibernation.
3. Assess the functionality of TLRs in complement and T-cell independent B-cell function during torpor and arousal.
4. Assess whether disruption of the S1P feed-forward system on any level precludes a T-cell response in sterile sepsis and thereby prevent kidney and lung damage.
5. Identify the role of tissue resident macrophages in the resistance of hibernators to ischemia-reperfusion damage.