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Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation

Philipp von Hundelshausen1,2, Stijn M Agten3, Veit Eckardt1

  • 1Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany.

Science Translational Medicine
|April 7, 2017
PubMed

Insights

Chemokine heterodimers modulate leukocyte activity, with CC-type enhancing and CXC-type inhibiting function. Targeting these specific chemokine interactions offers a novel therapeutic strategy for diseases like acute lung injury and atherosclerosis.

Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Chemokines regulate leukocyte movement and function in physiological and pathological conditions.
  • Interactions between different chemokines (heterophilic interactions) can alter their activity, but a complete map of these interactions is lacking.

Purpose of the Study:

  • To systematically map the chemokine interactome and characterize the functional consequences of chemokine heterodimerization.
  • To explore the potential of targeting chemokine interactions for therapeutic purposes.

Main Methods:

  • Immunoligand blotting and surface plasmon resonance were used to create a comprehensive map of chemokine-chemokine interactions.
  • Structure-function analyses were performed to understand how heterodimerization affects chemokine activity.

Main Results:

  • Chemokine activity is enhanced by CC-type heterodimers and inhibited by CXC-type heterodimers.
  • Specific heterodimers like CCL5-CCL17 induce functional synergism via receptor heteromerization, while CCL5-CXCL4 promotes retention via proteoglycan binding.
  • Inhibitory activity involves conformational changes affecting receptor signaling, as seen with CXCL12.
  • CC-type heterodimers drive acute lung injury and atherosclerosis, which were abrogated by specific peptide inhibitors or modified CXCL4.
  • Therapeutic strategies targeting CCL5-CCL17 and CXCL12 interactions showed promise in preclinical models.

Conclusions:

  • Chemokine heterodimerization differentially dictates functional outcomes, impacting leukocyte trafficking and disease pathogenesis.
  • Targeting specific chemokine heterodimers presents a promising avenue for developing novel therapeutics for inflammatory and cardiovascular diseases.

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