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-1 alpha/beta (SDF-1 alpha/beta) is phylogenetic ally a primitive chemokine widely expressed in a variety of tissues and cel l types, This expression is detectable in the absence of stimuli provided b y bacterial or viral infections and allergic or autoimmune disorders. Based on these and other findings, SDF-1 alpha has not been considered an inflam matory chemokine, but, rather, has been believed to be involved in certain homeostatic processes, such as leukocyte recirculation. SDF-1 alpha is a po tent chemoattractant for lymphocytes and monocytes that mediates its activi ty via the chemokine receptor CXCR4. Study of the role of SDF-1 alpha/CXCR4 in vivo during inflammation has been limited by the fact that transgenic m ice that have been made deficient in either molecule die early in life due to developmental defects. The present study was aimed at evaluating the fun ctional relevance of the SDF-1 alpha/CXCR4 axis during an inflammatory proc ess. Neutralizing Abs to CXCR4 reduced lung eosinophilia (bronchoalveolar l avage fluid and interstitium) by half, indicating that CXCR4-mediated signa ls contribute to lung inflammation in a mouse model of allergic airway dise ase (AAD). This reduction in inflammation was accompanied by a significant decrease in airway hyper-responsiveness. SDF-1 alpha neutralization resulte d in similar reduction in both lung allergic inflammation and airway hyperr esponsiveness. Retroviral delivery of a CXCR4 cDNA to leukocytes resulted i n greater inflammation when transduced mice were subjected to a mouse model of AAD, These results highlight that, although considered a noninflammator y axis, the involvement of CXCR4 and SDF-1 alpha Is critical during AAD, an d this receptor and its Ligand are potentially relevant in other inflammato ry processes.