Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice

Area of Science:

• Immunology
• Metabolic Disorders
• Sepsis Pathophysiology

Background:

• Obesity exacerbates sepsis severity and mortality.
• Sepsis progresses through hyper-inflammatory and hypo-inflammatory phases, with late-phase mortality being a critical concern.
• Sirtuins (SIRTs) are implicated in modulating sepsis transition, particularly in lean models.

Purpose of the Study:

• To investigate the role of sirtuins, specifically SIRT-2, in the transition from early to late sepsis in obese individuals.
• To determine if SIRT-2 inhibition during the hypo-inflammatory phase can improve immune function and survival in obese sepsis models.

Main Methods:

• Sepsis was induced via cecal ligation and puncture (CLP) in obese (ob/ob and diet-induced obese) and wild-type mice.
• Microvascular inflammation was assessed as a marker of immune function following LPS re-stimulation.
• SIRT-2 expression was analyzed during different sepsis phases, and its inhibition was tested during the hypo-inflammatory phase.

Main Results:

• Obese mice exhibited heightened early inflammation and a prolonged hypo-inflammatory phase compared to lean controls.
• SIRT-2 expression was elevated in obese mice during the hypo-inflammatory phase.
• Inhibition of SIRT-2 reversed suppressed microvascular inflammation and significantly improved 7-day survival in obese mice with sepsis.

Conclusions:

• SIRT-2 plays a crucial role in regulating microvascular inflammation during the hypo-inflammatory phase of sepsis in obese mice.
• Targeting SIRT-2 presents a potential novel therapeutic strategy for managing sepsis in obese patients.