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Induction of Accelerated Atherosclerosis in Mice: The "Wire-Injury" Model
Published on: August 25, 2020
Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice
Rory R Koenen1, Philipp von Hundelshausen, Irina V Nesmelova
1Institute for Cardiovascular Molecular Research, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Insights
Targeting chemokine heteromers, like those involving platelet factor-4 (PF4) and RANTES (CCL5), can reduce atherosclerosis. This approach offers a therapeutic strategy for chronic inflammation without compromising immune function.
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.
Abstract:
Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXCL4) and RANTES (CCL5), triggering monocyte arrest on inflamed endothelium. Homo-oligomerization is required for the recruitment functions of CCL5, and chemokine heteromerization has more recently emerged as an additional regulatory mechanism, as evidenced by a mutual modulation of CXCL8 and CXCL4 activities and by enhanced monocyte arrest resulting from CCL5-CXCL4 interactions. The CCL5 antagonist Met-RANTES reduces diet-induced atherosclerosis; however, CCL5 antagonism may not be therapeutically feasible, as suggested by studies using Ccl5-deficient mice which imply that direct CCL5 blockade would severely compromise systemic immune responses, delay macrophage-mediated viral clearance and impair normal T cell functions. Here we determined structural features of CCL5-CXCL4 heteromers and designed stable peptide inhibitors that specifically disrupt proinflammatory CCL5-CXCL4 interactions, thereby attenuating monocyte recruitment and reducing atherosclerosis without the aforementioned side effects. These results establish the in vivo relevance of chemokine heteromers and show the potential of targeting heteromer formation to achieve therapeutic effects.
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