The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis

Abstract

Research from over the past 20 years has implicated dipeptidyl peptidase (DPP) IV and its family members in many processes and different pathologies of the immune system. Most research has been focused on either DPPIV or just a few of its family members. It is, however, essential to consider the entire DPP family when discussing any one of its members. There is a substantial overlap between family members in their substrate specificity, inhibitors, and functions. In this review, we provide a comprehensive discussion on the role of prolyl-specific peptidases DPPIV, FAP, DPP8, DPP9, dipeptidyl peptidase II, prolyl carboxypeptidase, and prolyl oligopeptidase in the immune system and its diseases. We highlight possible therapeutic targets for the prevention and treatment of atherosclerosis, a condition that lies at the frontier between inflammation and cardiovascular disease.

Keywords: atherosclerosis; dipeptidyl peptidase; fibroblast activation protein α; immunophysiology; inflammation; prolyl carboxypeptidase; prolyl oligopeptidase.

Figure 1

The DPP family. Summary of the names, the localization, and most important field of action of all members of the DPP family. sDPPIV, soluble DPPIV; sFAP, soluble FAP; DPP9-L, long form of DPP9; N, nucleus; LYSO, lysosome; MT, microtubules; in, intracellular; out, extracellular.

Figure 2

Summary of CD26/DPPIV expression in cells of the immune system.

Figure 3

Overview of the expression and function of individual DPP family members in the innate immune system. Expression-based evidence is in italic.

Figure 4

Overview of in vitro data on DPP involvement in primary human T cell activation. (A) M6P/IGFIIR associates with mannose-6-phosphorylated DPPIV causing it to associate with CD45 in lipid rafts. This facilitates co-localization with the TCR signaling molecules for T cell costimulation. (B) Interaction of ADA presented by ADA-anchoring proteins on dendritic cells with DPPIV on T cells causes costimulation. (C) Interaction of DPPIV on T cells with caveolin-1 on monocytes induces the expression of CD86 on the latter. Interaction of CD86 with CD28 costimulates T cells. (D) Inhibition of DPP8/9 induces TGFβ in PWM-stimulated T cells. TGFβ attenuates T cell activation. (E) Inhibition or absence of DPPII steers T cells toward T_H17 differentiation.

Figure 5

Dipeptidyl peptidase inhibition as a putative strategy for the treatment of atherosclerosis. (1) DPP9 inhibition would attenuate M1 macrophage activation, reducing local inflammation. Reduction in TNFα would reduce FAP on smooth muscle cells (SMCs). This and FAP inhibition (2) would reduce collagen degradation and therefore plaque instability. PREP inhibition (3) would reduce neutrophil infiltration and consequently endothelial dysfunction and further monocyte infiltration. DPPIV inhibition (4) would prevent SMC proliferation, foam cell formation, endothelial dysfunction, and monocyte infiltration.