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SIRT2 Regulates EX VIVO PBMC Adhesion in Septic Shock Patients
Deepmala Shrestha1, Bishnu Pant1, Akash Ahuja1
1Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
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 intercellular adhesion molecule-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 from SS versus controls ± AK-7, we analyzed phagocytosis.
Results:
We found the following: (1) Muted plasma tumor necrosis factor and interleukin-1β-response to LPS in SS versus control (endotoxin tolerance); (2) endotoxin-tolerant SS-PBMCs exhibit high SIRT2 expression, and muted adhesion (adhesion tolerance), CD18 activation, and transmigration with LPS; and (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 monocyte-derived macrophages from SS patients.
Conclusions:
PBMC adhesion, a physiological biomarker, can be used to detect hypoinflammation. Defective PBMC and macrophage function in SS patients occur via high SIRT2 expression. SIRT2 inhibition is a potential therapeutic strategy for treating sepsis-associated hypo-inflammation.
