Critical involvement of the chemotactic axis CXCR4/stromal cell-derived factor-1 alpha in the inflammatory component of allergic airway disease.
Stromal cell-derived factor-1alpha/beta (SDF-1alpha/beta) is phylogenetically a primitive chemokine widely expressed in a variety of tissues and cell types. This expression is detectable in the absence of stimuli provided by bacterial or viral infections and allergic or autoimmune disorders. Based on these and other findings, SDF-1alpha has not been considered an inflammatory chemokine, but, rather, has been believed to be involved in certain homeostatic processes, such as leukocyte recirculation. SDF-1alpha is a potent chemoattractant for lymphocytes and monocytes that mediates its activity via the chemokine receptor CXCR4. Study of the role of SDF-1alpha/CXCR4 in vivo during inflammation has been limited by the fact that transgenic mice that have been made deficient in either molecule die early in life due to developmental defects. The present study was aimed at evaluating the functional relevance of the SDF-1alpha/CXCR4 axis during an inflammatory process. Neutralizing Abs to CXCR4 reduced lung eosinophilia (bronchoalveolar lavage fluid and interstitium) by half, indicating that CXCR4-mediated signals contribute to lung inflammation in a mouse model of allergic airway disease (AAD). This reduction in inflammation was accompanied by a significant decrease in airway hyper-responsiveness. SDF-1alpha neutralization resulted in similar reduction in both lung allergic inflammation and airway hyper-responsiveness. Retroviral delivery of a CXCR4 cDNA to leukocytes resulted in greater inflammation when transduced mice were subjected to a mouse model of AAD. These results highlight that, although considered a noninflammatory axis, the involvement of CXCR4 and SDF-1alpha is critical during AAD, and this receptor and its ligand are potentially relevant in other inflammatory processes.
Gonzalo
J A
JA
Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Lloyd
C M
CM
Peled
A
A
Delaney
T
T
Coyle
A J
AJ
Gutierrez-Ramos
J C
JC
D000281:Administration, Intranasal; D000595:Amino Acid Sequence; D000818:Animals; D000937:Antigen-Antibody Reactions; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000502:physiology*; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000276:immunology / Q000473:pathology; D006801:Humans; D007106:Immune Sera / Q000737:chemistry; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D007106:Immune Sera; D019718:Receptors, CXCR4; D010047:Ovalbumin