Proteolytic processing of CXCL11 by CD13/aminopeptidase N impairs CXCR3 and CXCR7 binding and signaling and reduces lymphocyte and endothelial cell migration.
CXCR3 ligands were secreted by tissue fibroblasts and peripheral blood-derived mononuclear leukocytes in response to interferon-gamma (IFN-gamma) and Toll-like receptor (TLR) ligands. Subsequent purification and identification revealed the presence of truncated CXCL11 variants missing up to 6 amino acids. In combination with CD26/dipeptidyl peptidase IV, the metalloprotease aminopeptidase N (APN), identical to the myeloid cell marker CD13, rapidly processed CXCL11, but not CXCL8, to generate truncated CXCL11 forms. Truncated CXCL11 had reduced binding, signaling, and chemotactic properties for lymphocytes and CXCR3- or CXCR7-transfected cells. CD13/APN-truncated CXCL11 failed to induce an intracellular calcium increase but was still able to bind and desensitize CXCR3 for intact CXCL11 signaling. CXCL11 efficiently bound to CXCR7, but CXCL11 was not able to induce calcium signaling or ERK1/2 or Akt phosphorylation through CXCR7. CD26-truncated CXCL11 failed to attract lymphocytes but still inhibited microvascular endothelial cell (HMVEC) migration. However, further processing of CXCL11 by CD13 resulted in significant reduction of inhibition of HMVEC migration. Taken together, during inflammation or cancer, CXCL11 processing by CD13 may lead to a reduced number of tumor-infiltrating lymphocytes and in a more angiogenic environment.
Proost
Paul
P
Laboratory of Molecular Immunology, Rega Institute, University of Leuven, Leuven, Belgium. paul.proost@rega.kuleuven.be
Mortier
Anneleen
A
Loos
Tamara
T
Vandercappellen
Jo
J
Gouwy
Mieke
M
Ronsse
Isabelle
I
Schutyser
Evemie
E
Put
Willy
W
Parmentier
Marc
M
Struyf
Sofie
S
Van Damme
Jo
J
D018826:CD13 Antigens / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology; D014644:Genetic Variation; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D009369:Neoplasms / Q000473:pathology; D011499:Protein Processing, Post-Translational; D054387:Receptors, CXCR; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction
C501896:ACKR3 protein, human; C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; D054387:Receptors, CXCR; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; D018826:CD13 Antigens