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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.
Shock (Augusta, Ga.)
|December 29, 2025
Summary
Septic shock (SS) involves immune cells becoming hypo-inflammatory. High SIRT2 expression in SS patients impairs immune cell function, but inhibition may offer a therapeutic strategy for sepsis-induced hypo-inflammation.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- Septic shock (SS) is a life-threatening condition characterized by a shift in immune response from hyper-inflammation to hypo-inflammation.
- Sirtuin 2 (SIRT2) has been implicated in prolonged hypo-inflammation in mouse models of sepsis.
- The role of SIRT2 in human sepsis and its impact on immune cell function remain largely unknown.
Purpose of the Study:
- To investigate the potential of peripheral blood mononuclear cell (PBMC) adhesion as a biomarker for hypo-inflammation in human sepsis.
- To determine if SIRT2 regulates PBMC and macrophage function during the hypo-inflammatory phase of human sepsis.
Main Methods:
- Whole blood and PBMCs from control and SS patients were stimulated with lipopolysaccharide (LPS) to assess plasma cytokines, PBMC adhesion, CD18 activation, and SIRT2 expression.
- Adhesion and endotoxin-tolerant PBMCs, along with THP-1 cells, were treated with a SIRT2 inhibitor (AK-7) to analyze cell adhesion, CD18 activation, and transmigration.
- Monocyte-derived macrophages (MDMs) from SS patients were analyzed for phagocytosis with and without AK-7 treatment.
Main Results:
- SS patients exhibited endotoxin tolerance, characterized by muted plasma cytokine responses (TNF, IL-1β) to LPS.
- Endotoxin-tolerant PBMCs from SS patients showed high SIRT2 expression, reduced adhesion, CD18 activation, and transmigration in response to LPS.
- SIRT2 inhibition with AK-7 reversed endotoxin and adhesion tolerance in SS PBMCs, restored PBMC transmigration, and improved macrophage phagocytosis in SS patients.
Conclusions:
- PBMC adhesion serves as a reliable physiological biomarker for detecting hypo-inflammation in septic shock.
- Elevated SIRT2 expression contributes to the defective function of PBMCs and macrophages in septic shock patients.
- Targeting SIRT2 with inhibitors presents a promising therapeutic avenue for managing sepsis-associated hypo-inflammation.
