Session Speaker

Role of SphK1 in TLRs Signalling and Sepsis: Therapeutic Inhibition of SphK1 is Protective in Experimental Endotoxin Shock and Polymicrobial Sepsis
Padmam Puneet and Alirio J. Melendez
UK

The incidence of sepsis, and death due to septic-shock, has seen a dramatic increase over the past few decades 1, 2. During sepsis, host’s innate responses to bacterial infections are primarily mediated by neutrophils and monocytes/macrophages3. These cells express pattern recognition receptors (PRRs) that bind conserved molecular structures shared by groups of micro-organisms3. Upon stimulation, PRRs initiate inflammatory signaling pathways leading to secretion of proinflammatory mediators, which promote the elimination of infectious agents and the induction of tissue repair. However, excessive production of inflammatory mediators, such as TNF?, IL-1?? the anaphylatoxin C5a and the high mobility group 1 protein (HMGB1), can induce septic-shock by triggering a systemic inflammation-mediating vascular leakage, tissue damage, multi-organ failure and death4,5. We and others have shown that several proinflammatory stimuli, including C5a, TNF?, and immune-complexes, activate sphingosine kinase 1 (SphK1) on human neutrophils and macrophages, and that blockade of SphK1 inhibits several proinflammatory responses triggered by these stimuli6-12. SphKs are intracellular signaling enzymes that generate the potent lipid mediator sphingosine-1-phospahate (S1P). Here we show that SphK1 is upregulated, in monocytes and neutrophils, by bacterial products, as well as in peritoneal monocytes and neutrophils of human patients with microbial sepsis and mice with experimental septic-shock. Blockade of SphK1 inhibits the overall inflammatory response to bacterial endotoxin. Furthermore, inhibition of SphK1 protects mice against polymicrobial sepsis caused by cecal ligation and puncture. Finally, inhibiting SphK1 after the initiation of experimental sepsis, using our novel SphK1-specific inhibitor (5c) protects mice in a therapeutic manner, and co-administration of 5c with a broad spectrum antibiotic dramatically increases survival from sepsis, greatly enhancing the time-window for treatment. These results demonstrate a critical function of SphK1 in acute inflammatory responses in polymicrobial sepsis, and validate our specific SphK1-inhibitor alone, or in combination with antibiotics, as potential novel treatments in septic shock.