Vascular dysfunction following polymicrobial sepsis: role of pattern recognition receptors

Area of Science:

• Immunology
• Vascular Biology
• Sepsis Pathophysiology

Background:

• Polymicrobial sepsis leads to significant vascular dysfunction.
• Pattern recognition receptors (PRRs) are implicated in sepsis pathogenesis.
• The specific roles of individual PRRs in sepsis-induced vascular dysfunction require further elucidation.

Purpose of the Study:

• To investigate the precise role of pattern recognition receptors (PRRs) in vascular dysfunction during polymicrobial sepsis.
• To determine the impact of Toll-like receptor (TLR) 2, 4, and 9 deficiencies, as well as CD14 deficiency, on sepsis-induced vascular dysfunction.

Main Methods:

• Utilized a colon ascendens stent peritonitis (CASP) model in C57BL/6 mice and mice deficient in TLR2, TLR4, TLR9, or CD14.
• Assessed vascular contractility 18 hours post-CASP.
• Quantified mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), anti-inflammatory cytokine (IL-10), and inducible nitric oxide synthase (iNOS) via RT-qPCR.
• Administered a TLR9 antagonist (H154-ODN) to wildtype mice to evaluate its therapeutic potential.

Main Results:

• Wildtype mice showed significant loss of vascular contractility post-CASP.
• TLR2-deficient mice exhibited aggravated vascular dysfunction and increased pro-inflammatory cytokine and iNOS expression.
• TLR4-deficient mice displayed blunted vascular dysfunction, while TLR9- and CD14-deficient mice showed abolished dysfunction.
• TLR9 antagonism with H154-ODN attenuated sepsis-induced cytokine release and vascular dysfunction in wildtype mice.

Conclusions:

• CD14 and TLR9 play critical roles in the development of vascular dysfunction during polymicrobial sepsis.
• TLR9 can be effectively antagonized using H154-ODN, offering a potential therapeutic strategy.
• TLR2-deficient mice are more susceptible to sepsis, likely due to compensatory upregulation of TLR4, TLR9, and CD14.