Dipeptidyl Peptidase-4 Regulation of SDF-1/CXCR4 Axis: Implications for Cardiovascular Disease

Zhong, Jixin; Rajagopalan, Sanjay

Dipeptidyl peptidase-4 has been shown to be able to cleave a number of chemokines and cytokines, including SDF-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin-3 (IL-3), erythropoietin (Epo), regulated on activation normal T-cell expressed and presumably secreted (RANTES, also known as CCL5), macrophage-derived chemokine (MDC, also known as CCL22), eotaxin (also known as CCL11), monokine induced by IFN-γ (MIG, also known as CXCL9), IFN-γ-induced protein-10 (IP-10, also known as CXCL10), and interferon-inducible T-cell α chemoattractant (ITAC, also known as CXCL11) ( Table 2 ). The regulation of cytokine levels through catalytic cleavage may influence their levels in tissue domains. The differential contribution of DPP4 in the regulation of each of these cytokines is obviously dependent on the levels of expression of DPP4, which may vary depending on the tissues, the cells predominantly expressing the cytokine of interest and the disease context. Additionally, circulating or cell free DPP4 may also contribute to catalytic activity. DPP4-mediated truncation of RANTES abolishes the chemotactic activity to monocytes but not to T cells (27) . Eotaxin (CCL11) is an eosinophil chemotactic protein and has been shown to be involved in allergic responses. DPP4 truncation of eotaxin inactivates its chemotactic activity for eosinophils. DPP4-truncated eotaxin shows impaired binding and signaling through CCR3. In addition, truncated eotaxin suppresses calcium signaling and chemotaxis of intact eotaxin (28) . DPP4 inhibition by either genetic deletion or pharmacological inhibition, enhances eotaxin-induced mobilization of eosinophils into the blood and recruitment into the injury/injection site (29) . MDC (CCL22) is a chemoattractant for monocytes, dendritic cells, NK cells, and chronically activated T lymphocytes (30, 31) . DPP4-truncated MDC displays preserved chemotactic activity toward monocytes, but less potency toward lymphocytes and dendritic cells (32) . CXCR3 interacts with MIG (CXCL9), IP10 (CXCL10), and ITAC (CXCL11), all of which are targets of DPP4. Cleavage of those chemokines by DPP4 attenuates their chemotactic activity, with the cleaved products serving as endogenous antagonists for CXCR3 binding (33) . Dipeptidyl peptidase-4 is also involved in the inactivation of multiple colony-stimulating factors (CSFs) and thus regulates hematopoietic stem cells (HSCs) and hematopoietic progenitor cell (HPC) function. The proliferative action of GM-CSF, G-CSF, IL-3, and Erythropoietin (Epo) on HPCs is enhanced in DPP4 knockout mice or by pretreatment with a DPP4 inhibitor (35) . Catalytic inhibition of DPP4 or DPP4 deficiency promotes the engraftment of HSCs and HPCs after bone marrow transplantation in mice (35) . DPP4-truncated CSFs may suppress the activity of their respective full-length CSF via antagonism (35) .