Anti-inflammatory therapy by intravenous delivery of non-heparan sulfate-binding CXCL12.
Interaction between chemokines and heparan sulfate (HS) is essential for leukocyte recruitment during inflammation. Previous studies have shown that a non-HS-binding mutant form of the inflammatory chemokine CCL7 can block inflammation produced by wild-type chemokines. This study examined the anti-inflammatory mechanism of a non-HS-binding mutant of the homeostatic chemokine CXCL12. Initial experiments demonstrated that mutant CXCL12 was an effective CXCR4 agonist. However, this mutant chemokine failed to promote transendothelial migration in vitro and inhibited the haptotactic response to wild-type CCL7, CXCL12, and CXCL8, and naturally occurring chemoattractants in synovial fluid from the rheumatoid synovium, including CCL2, CCL7, and CXCL8. Notably, intravenous administration of mutant CXCL12 also inhibited the recruitment of leukocytes to murine air pouches filled with wild-type CXCL12. Following intravenous administration, wild-type CXCL12 was cleared from the circulation rapidly, while the mutant chemokine persisted for >24 h. Chronic exposure to mutant CXCL12 in the circulation reduced leukocyte-surface expression of CXCR4, reduced the chemotactic response of these cells to CXCL12, and inhibited normal chemokine-mediated induction of adhesion between the alpha4beta1 integrin, VLA-4, and VCAM-1. These data demonstrate that systemic administration of non-HS-binding variants of CXCL12 can mediate a powerful anti-inflammatory effect through chemokine receptor desensitization.
O'Boyle
Graeme
G
Applied Immunobiology and Transplantation Research Group, Institute of Cellular Medicine, Medical School, University of Newcastle, Newcastle upon Tyne, NE2 4HH UK.
Mellor
Paul
P
Kirby
John A
JA
Ali
Simi
S
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016466:CHO Cells; D054377:Chemokine CXCL12 / Q000008:administration & dosage / Q000235:genetics* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D004727:Endothelium / Q000378:metabolism; D005260:Female; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D039041:Integrin alpha4beta1 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D019718:Receptors, CXCR4 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D054377:Chemokine CXCL12; D006497:Heparan Sulfate; D039041:Integrin alpha4beta1; D019718:Receptors, CXCR4