Toll-like Receptor 7 Deficiency Attenuates Platelet Dysfunction in Sepsis

Area of Science:

• Immunology
• Hematology
• Pathophysiology

Background:

• Sepsis involves abnormal host response to infection, often leading to thrombocytopenia and platelet dysfunction, which worsen patient outcomes.
• Toll-like Receptor-7 (TLR7), an innate immune sensor, is implicated in sepsis-related thrombocytopenia.
• The role of TLR7 in sepsis-induced platelet dysfunction and the impact on extracellular vesicle (EV) bioactivity remain unclear.

Purpose of the Study:

• To investigate the contribution of TLR7 signaling to platelet dysfunction in sepsis.
• To determine if TLR7 signaling affects the bioactivity of sepsis-associated extracellular vesicles (EVs).

Main Methods:

• Sepsis was induced in wild-type and TLR7-deficient mice via cecal ligation and puncture.
• Platelet function was assessed through aggregation, adhesion, and calcium flux assays.
• Extracellular vesicles (EVs) were isolated from plasma and their role in platelet-leukocyte aggregate (PLA) formation was evaluated in vitro.

Main Results:

• Septic platelets exhibited hyperactivation and increased adhesion but impaired aggregation and calcium signaling, indicative of functional exhaustion.
• TLR7-deficient mice showed preserved platelet aggregation, enhanced adhesion, and maintained calcium release compared to wild-type controls.
• Sepsis increased plasma EV abundance and size, promoting clot and PLA formation; this EV-mediated platelet activation was reduced when using EVs from TLR7-deficient mice.

Conclusions:

• Sepsis induces persistent platelet activation and dysfunction, which is partially mitigated by TLR7 deficiency.
• TLR7 signaling critically modulates the pathogenic activity of EVs in sepsis, impacting platelet function.
• Targeting TLR7 may offer a therapeutic strategy to preserve platelet function and mitigate adverse outcomes in sepsis.