Sirtuin 1 deletion increases inflammation and mortality in sepsis

Area of Science:

• Biomedical research
• Immunology
• Renal medicine

Background:

• Sepsis triggers a dangerous hyperinflammatory response, often leading to multiorgan failure and death.
• Renal dysfunction frequently precedes multiorgan failure in sepsis.
• Sirtuin 1 (SIRT1) is known to enhance cellular resilience by reducing inflammation and improving mitochondrial function.

Purpose of the Study:

• To investigate the role of SIRT1 in mitigating sepsis-induced organ failure.
• To determine if SIRT1's protective effects in sepsis are primarily mediated by its expression in myeloid cells.

Main Methods:

• Cecal ligation and puncture (CLP) was performed on wild-type, whole-body SIRT1 knockout (S1KO), and myeloid cell-specific S1KO (S1KO-LysMCre) mice.
• Serum levels of interleukin-6 (IL-6), blood urea nitrogen (BUN), and renal mitochondrial respiratory capacity were measured.
• Survival rates were monitored for five days post-CLP.

Main Results:

• SIRT1 deletion in mice led to impaired renal mitochondrial respiration and increased blood urea nitrogen levels.
• Sepsis induced higher IL-6 levels in S1KO and S1KO-LysMCre mice compared to controls.
• Five-day survival was significantly reduced in both S1KO and S1KO-LysMCre mice following CLP.

Conclusions:

• SIRT1 deletion exacerbates systemic inflammation, renal mitochondrial dysfunction, kidney injury, and mortality in a sepsis model.
• The protective role of SIRT1 in sepsis appears to be significantly influenced by its activity within myeloid cells.