Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice

Area of Science:

• Immunology
• Cardiovascular Biology
• Structural Biology

Background:

• Atherosclerosis involves chronic arterial inflammation driven by chemokine-mediated mononuclear cell recruitment.
• Activated platelets enhance atherogenesis by depositing chemokines like PF4 (CXCL4) and CCL5, promoting monocyte adhesion.
• Chemokine heteromerization, such as CCL5-CXCL4 interactions, modulates activity and increases monocyte arrest.

Purpose of the Study:

• To investigate the structural basis of CCL5-CXCL4 heteromers.
• To design peptide inhibitors that specifically disrupt pro-inflammatory CCL5-CXCL4 interactions.
• To evaluate the therapeutic potential of targeting chemokine heteromer formation in atherosclerosis.

Main Methods:

• Structural determination of CCL5-CXCL4 heteromers.
• Design and synthesis of peptide inhibitors targeting these heteromers.
• Assessment of monocyte recruitment in vitro and atherosclerosis reduction in vivo.

Main Results:

• Structural insights into CCL5-CXCL4 heteromer formation were obtained.
• Stable peptide inhibitors effectively disrupted pro-inflammatory CCL5-CXCL4 interactions.
• These inhibitors attenuated monocyte recruitment and reduced diet-induced atherosclerosis in vivo.
• Therapeutic intervention avoided systemic immune side effects associated with direct CCL5 antagonism.

Conclusions:

• Chemokine heteromers play a significant role in atherogenesis.
• Targeting heteromer formation offers a novel therapeutic strategy for atherosclerosis.
• This approach provides a way to reduce inflammation without broad immune suppression.