Role of the Neutrophil Chemorepellent Soluble Dipeptidyl Peptidase IV in Decreasing Inflammation in a Murine Model of Arthritis

Abstract

Objective To determine whether an intraarticular injection of the neutrophil chemorepellent dipeptidyl peptidase IV (DPPIV; CD26) can attenuate inflammation and decrease the severity of arthritis in a murine model. Methods DBA/1 mice were immunized with type II collagen/Freund's complete adjuvant to produce collagen-induced arthritis (CIA). On day 25 postimmunization, recombinant human DPPIV (rhDPPIV) or phosphate buffered saline was injected intraarticularly, and arthritis severity scores were recorded 3 times per week. The hind legs of mice in both groups were fixed, decalcified, paraffin embedded, and sectioned. Pathologic scores for inflammation and neutrophil infiltration were recorded on a scale of 1–8, and the number of neutrophils was determined by morphometric cell counts. In addition, Mac-2–positive macrophages and articular damage were assessed using anti–Mac-2 antibodies and histologic staining, respectively. Results Injection of rhDPPIV reduced the mean score of arthritis severity in mice with CIA. DPPIV treatment reduced the overall extent of inflammation and articular damage around the arthritic joint and periarticular tissue, and also decreased neutrophil and macrophage infiltration. Conclusion A localized injection of the neutrophil chemorepellent DPPIV reduces inflammation and the severity of the disease in a murine model of arthritis.

Progenitor Cells Activated by Platelet Lysate in Human Articular Cartilage as a Tool for Future Cartilage Engineering and Reparative Strategies

“…DPPIV release was also significantly higher in CPCs-PL than in ACs-PL. In a murine model of collagen-induced arthritis (CIA), it has been demonstrated that DPPIV injection decreases the overall extent of inflammation and articular damage around the arthritic joint and periarticular tissue [83].…”

Activity and expression of dipeptidyl peptidase IV on peripheral blood mononuclear cells in patients with early steroid and disease modifying antirheumatic drugs naïve rheumatoid arthritis

“…Low levels of DPPIV activity or soluble CD26 were observed in immuno-suppressed conditions including some tumors; whereas high levels occur in other tumors, infectious, inflammatory and liver diseases [2]. These qualitative or quantitative changes may be important in the pathogenesis of RA, since DPPIV as a result of its N-terminal X-Pro cleaving activity regulates chemotactic responses to the inflammatory chemokines CCL3- 5,11 and 22,CXCL2,[9][10][11][12], including SDF-1 [24,25]. In addition, it regulates other biologically active peptides such as NPY and VIP, recently implicated in RA [26].…”

“…In synovial tissue and in synovial fluid, significantly lower expression and membrane activity of CD26 were detected on mononuclear cells of synovial fluid [10]. Furthermore, inhibition of synovial DPPIV activity had led to increased cartilage destruction, pointing to DPPIV as a protective factor of articular cartilage [11,12].…”

Extracellular signaling in Dictyostelium

“…Being able to repel neutrophils out of the affected tissue might be therapeutic. Treatment with inhaled DPPIV prevented an increase in lung neutrophils in a mouse model of ARDS (Herlihy et al, 2013a), and localized injections of DPPIV decreased symptoms of arthritis in a mouse model (Herlihy et al, 2015). We then found that the DPPIV receptor is the proteaseactivated G protein-coupled receptor PAR 2, that PAR 2 agonists induce human neutrophil chemorepulsion, and when administered by aspiration into the airways, PAR 2 agonists show good efficacy at reducing the inappropriate influx of neutrophils into the lungs in a mouse model of ARDS (White et al, 2018).…”