Simultaneous targeting of IL-1 and IL-18 is required for protection against inflammatory and septic shock

Area of Science:

• Immunology
• Molecular Biology
• Pathophysiology

Background:

• Sepsis is a leading global cause of mortality, with complex and poorly understood molecular mechanisms hindering effective clinical treatments.
• Existing therapeutic strategies for sepsis have largely failed, highlighting the urgent need to elucidate its underlying molecular pathways.

Purpose of the Study:

• To determine the hierarchical roles of key inflammatory mediators, including IL-1β, IL-18, CASP1, and CASP11, in the pathogenesis of septic shock.
• To evaluate the therapeutic potential of targeting these mediators in preclinical models of sepsis.

Main Methods:

• Lethal endotoxin (LPS) and tumor necrosis factor (TNF)-induced shock models were employed in genetically modified or pharmacologically treated mice.
• Cecal ligation and puncture (CLP) was utilized as a severe sepsis model in mice.
• Physiological parameters (body temperature, survival) and plasma inflammatory markers were closely monitored.

Main Results:

• Mice deficient in both IL-1β and IL-18 showed significantly reduced mortality from LPS-induced shock.
• The protective effect of IL-1β and IL-18 deficiency was confirmed in TNF-induced and CLP sepsis models.
• Mice lacking CASP1 or CASP11 exhibited minimal protection against lethal TNF or CLP challenges, suggesting limited therapeutic value.
• Combined blockade of IL-1 and IL-18 using anakinra and anti-IL-18 antibodies provided complete protection against endotoxin lethality.

Conclusions:

• Simultaneous neutralization of IL-1 and IL-18 represents a promising therapeutic strategy for sepsis.
• Targeting upstream inflammatory caspases (CASP1, CASP11) is less effective than targeting IL-1 and IL-18 directly in sepsis treatment.