A GPVI-platelet-neutrophil-NET axis drives systemic sclerosis

Area of Science:

• Immunology
• Rheumatology
• Pathology

Background:

• Systemic sclerosis (SSc) is a severe autoimmune disease with high mortality due to progressive organ fibrosis.
• Current understanding of SSc pathogenesis, particularly the cellular mechanisms driving fibrosis, remains incomplete.

Purpose of the Study:

• To elucidate the roles of neutrophils and platelets in SSc pathogenesis.
• To identify key molecular pathways and effector mechanisms driving SSc fibrosis.
• To explore potential therapeutic targets for SSc.

Main Methods:

• Analysis of neutrophil and platelet activation in SSc patients and murine models.
• Transcriptomic analysis of affected tissues.
• Experimental models using neutrophil depletion, platelet depletion, and PAD4 knockout mice.
• Adoptive transfer of neutrophils and platelets.
• Assessment of neutrophil extracellular traps (NETs) and GPVI signaling.

Main Results:

• Neutrophil activation is a hallmark of SSc, with SSc neutrophils inducing fibrosis in mice.
• Platelet activation precedes and drives neutrophil activation and fibrosis.
• Neutrophil extracellular traps (NETs) are essential effector mechanisms in SSc.
• Platelet collagen receptor GPVI mediates platelet and neutrophil activation, crucial for SSc development.

Conclusions:

• A novel GPVI-platelet-neutrophil-NET axis is identified as central to SSc pathogenesis.
• Neutrophils, platelets, and NETs are necessary and sufficient for driving SSc fibrosis.
• Targeting this axis, particularly GPVI, offers a promising therapeutic strategy for SSc.