SIRT2 Regulates Ex Vivo PBMC Adhesion in Septic Shock Patients.

BACKGROUND: Septic shock (SS) is deadly. Sepsis-immune response transitions from an endotoxin-sensitive, hyper-inflammatory phase to an endotoxin-tolerant hypo-inflammatory phase. In mice, we implicated sirtuin 2 (SIRT2) for prolonged hypo-inflammation using leukocyte adhesion, the earliest in vivo inflammatory response to cytokine, chemokine, and metabolite stimuli. The role of SIRT2 in human sepsis remains unknown. We hypothesized that: 1. Peripheral blood mononuclear cells (PBMCs) adhesion response can be used as a physiological biomarker of hypo-inflammation, and 2. SIRT2 regulates the functions of PBMCs and macrophages during the hypo-inflammatory phase of human sepsis. METHODS: We stimulated control and SS-whole blood and PBMCs ± lipopolysaccharide (LPS) and investigated plasma cytokines, PBMC cell adhesion to ICAM-1 coated plates, adhesion molecule CD18 activation, SIRT2 expression, and cytokine response. In adhesion/endotoxin-tolerant PBMCs and THP-1 cells treated ± SIRT2 inhibitor AK-7, we analyzed cell adhesion, CD18 activation, and transmigration ± LPS. In monocyte-derived macrophages (MDMs) from SS vs. controls ± AK-7, we analyzed phagocytosis. RESULTS: We found: 1. Muted plasma TNF and IL-1β-response to LPS in SS vs. control (endotoxin-tolerance) 2. Endotoxin-tolerant SS-PBMCs exhibit high SIRT2 expression, and muted adhesion (adhesion-tolerance), CD18 activation, and transmigration with LPS. 3. SIRT2 inhibitor AK-7 reverses endotoxin and adhesion-tolerance in SS-PBMCs via CD18 activation, reverses the defective transmigration of endotoxin-tolerant PBMCs and improves phagocytosis in MDMs from SS patients. CONCLUSION: PBMC adhesion, a physiological biomarker, can be used to detect hypo-inflammation. Defective PBMC and macrophage function in septic shock patients occur via high SIRT2 expression. SIRT2 inhibition is a potential therapeutic strategy for treating sepsis-associated hypo-inflammation.