Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1

Chemokines provide directional cues for leukocyte migration and activation that are essential for normal leukocytic trafficking and for host responses during processes such as inflammation, infection, and cancer. Recently we reported that matrix metalloproteinases (MMPs) modulate the activity of the CC chemokine monocyte chemoattractant protein-3 by selective proteolysis t o release the N-terminal tetrapeptide. Here we report the N-terminal proces sing, also at position 4-5, of the CXC chemokines stromal cell-derived fact or (SDF)-1 alpha and beta by MMP-2 (gelatinase A). Robustness of the MMP fa mily for chemokine cleavage was revealed from identical cleavage site speci ficity of MMPs 1, 3, 9, 13, and 14 (MT1-MMP) toward SDF-1; selectivity was indicated by absence of cleavage by AMP's 7 and 8. Efficient cleavage of SD F-1 alpha by MMP-2 is the result of a strong interaction with the NMP hemop exin C domain at an exosite that overlaps the monocyte chemoattractant prot ein-3 binding site. The association of SDF-1 alpha with different glycosami noglycans did not inhibit cleavage. MMP cleavage of SDF-1 alpha resulted in loss of binding to its cognate receptor CXCR-4. This was reflected in a lo ss of chemoattractant activity for CD34(+) hematopoietic progenitor stem ce lls and pre-B cells, and unlike full-length SDF-1 alpha, the MMP-cleaved ch emokine was unable to block CXCR-4-dependent human immunodeficiency virus-1 infection of CD4(+) cells. These data suggest that MMPs may be important r egulatory proteases in attenuating SDF-1 function and point to a deep conve rgence of two important networks, chemokines and MMPs, to regulate leukocyt ic activity in vivo.