Harmful Roles of TLR3 and TLR9 in Cardiac Dysfunction Developing during Polymicrobial Sepsis

Area of Science:

• Immunology
• Cardiology
• Pathophysiology

Background:

• Septic cardiomyopathy is a severe complication of sepsis.
• Its progression is linked to complement system activation and histone release.
• Toll-like receptors (TLRs) play a role in sepsis pathogenesis.

Purpose of the Study:

• To investigate the roles of TLR3 and TLR9 in the development of septic cardiomyopathy.
• To determine the impact of TLR3 and TLR9 deficiency on sepsis-induced cardiac dysfunction and associated molecular changes.

Main Methods:

• Polymicrobial sepsis was induced in wild-type, TLR3-knockout, and TLR9-knockout mice using cecal ligation and puncture (CLP).
• Echocardiogram (Echo)-Doppler was used to assess cardiac function.
• Plasma levels of C5a, histones, and cytokines were measured.
• Rat cardiomyocytes were exposed to histones in vitro to assess direct cellular effects.

Main Results:

• Absence of TLR3 or TLR9 significantly reduced cardiac dysfunction in CLP mice.
• TLR3- and TLR9-knockout mice exhibited lower plasma levels of C5a, histones, and cytokines post-CLP.
• In vitro, histones induced bleb formation and lactate dehydrogenase release from cardiomyocytes, indicating cell membrane damage.

Conclusions:

• TLR3 and TLR9 are essential for sepsis-induced cardiac dysfunction.
• The findings suggest a mechanism involving TLR3/TLR9, complement activation, histone release, and subsequent cardiomyocyte damage.
• Targeting TLR3 and TLR9 may offer a therapeutic strategy for septic cardiomyopathy.