Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation.
Philipp Von HundelshausenStijn M AgtenVeit EckardtXavier BlanchetMartin M SchmittHans IppelCarlos NeideckKiril BidzhekovJulian LeberzammerKanin WichapongAlexander FaussnerMaik DrechslerJochen GrommesJohanna P van GeffenHe LiAlmudena Ortega-GomezRemco T A MegensRonald NaumannIngrid DijkgraafGerry A F NicolaesYvonne DöringOliver SoehnleinEsther LutgensJohan W M HeemskerkRory R KoenenKevin H MayoTilman M HackengChristian WeberPublished in: Science translational medicine (2017)
Chemokines orchestrate leukocyte trafficking and function in health and disease. Heterophilic interactions between chemokines in a given microenvironment may amplify, inhibit, or modulate their activity; however, a systematic evaluation of the chemokine interactome has not been performed. We used immunoligand blotting and surface plasmon resonance to obtain a comprehensive map of chemokine-chemokine interactions and to confirm their specificity. Structure-function analyses revealed that chemokine activity can be enhanced by CC-type heterodimers but inhibited by CXC-type heterodimers. Functional synergism was achieved through receptor heteromerization induced by CCL5-CCL17 or receptor retention at the cell surface via auxiliary proteoglycan binding of CCL5-CXCL4. In contrast, inhibitory activity relied on conformational changes (in CXCL12), affecting receptor signaling. Obligate CC-type heterodimers showed high efficacy and potency and drove acute lung injury and atherosclerosis, processes abrogated by specific CCL5-derived peptide inhibitors or knock-in of an interaction-deficient CXCL4 variant. Atheroprotective effects of CCL17 deficiency were phenocopied by a CCL5-derived peptide disrupting CCL5-CCL17 heterodimers, whereas a CCL5 α-helix peptide mimicked inhibitory effects on CXCL12-driven platelet aggregation. Thus, formation of specific chemokine heterodimers differentially dictates functional activity and can be exploited for therapeutic targeting.
Keyphrases
- liver injury
- liver fibrosis
- drug induced
- randomized controlled trial
- healthcare
- public health
- type diabetes
- magnetic resonance
- oxidative stress
- lipopolysaccharide induced
- cell surface
- high resolution
- molecular dynamics
- risk assessment
- computed tomography
- magnetic resonance imaging
- inflammatory response
- health information
- climate change
- high density