The unique structural and functional features of CXCL12

The CXC chemokine CXCL12 is an important factor in physiological and pathological processes, includingembryogenesis, hematopoiesis, angiogenesis and inflammation, because it activates and/or induces migration ofhematopoietic progenitor and stem cells, endothelial cells and most leukocytes. Therefore, CXCL12 activity istightly regulated at multiple levels. CXCL12 has the unique property of existing in six splice variants in humans,each having a specific tissue distribution and in vivo activity. Controlled splice variant transcription and mRNAstability determine the CXCL12 expression profile. CXCL12 fulfills its functions in homeostatic and pathologicalconditions by interacting with its receptors CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3(ACKR3) and by binding to glycosaminoglycans (GAGs) in tissues and on the endothelium to allow a properpresentation to passing leukocytes. Homodimerizaton and heterodimerization of CXCL12 and its receptors can altertheir signaling activity, as exemplified by the synergy between CXCL12 and other chemokines in leukocyte migrationassays. Receptor binding may also initiate CXCL12 internalization and its subsequent removal from theenvironment. Furthermore, CXCL12 activity is regulated by posttranslational modifications. Proteolytic removal ofNH2- or COOH-terminal amino acids, citrullination of arginine residues by peptidyl arginine deiminases or nitrationof tyrosine residues reduce CXCL12 activity. This review summarizes the interactions of CXCL12 with the cellularenvironment and discusses the different levels of CXCL12 activity regulation.