KLF7-IT1-ARPC2 axis in macrophages orchestrates caspase-4-driven hypercoagulation in sepsis

Area of Science:

• Molecular Biology
• Immunology
• Pathophysiology

Background:

• Sepsis involves dysregulated inflammation and coagulation, leading to organ dysfunction.
• Molecular mechanisms linking inflammation and coagulation in sepsis are not fully understood.

Purpose of the Study:

• Identify novel molecular regulators of sepsis-induced coagulopathy.
• Elucidate the role of long non-coding RNAs in sepsis pathogenesis.

Main Methods:

• Transcriptomic profiling of leukocytes from septic and non-septic patients.
• In vitro functional studies on KLF7-IT1, caspase-4, gasdermin-D, ARPC2, and neutrophil extracellular traps (NETs).
• Assessment of procoagulant activity, pyroptosis, and cytoskeletal remodeling.

Main Results:

• KLF7-IT1 is significantly upregulated in sepsis and correlates with hypercoagulability and organ injury.
• KLF7-IT1 enhances macrophage procoagulant activity via caspase-4 activation, pyroptosis, and ARPC2 stabilization.
• KLF7-IT1 promotes LPS internalization, pyroptosis, and amplifies macrophage-neutrophil crosstalk, inducing NET formation.

Conclusions:

• KLF7-IT1 integrates cytoskeletal remodeling, pyroptosis, and NETosis, creating a procoagulant network in sepsis.
• The KLF7-IT1-ARPC2-caspase-4 axis is a novel pathway linking endotoxin sensing to pyroptotic cell death and coagulation.
• Targeting this axis offers a potential therapeutic strategy for sepsis-associated organ failure.