Treatment with a Urokinase Receptor-derived Cyclized Peptide Improves Experimental Colitis by Preventing Monocyte
Marco Genua1, Vincenzo Ingangi, Philippe Fonteyne
1*IBD Center, Humanitas Research Institute, Rozzano, Italy; †Department of Translational Medicine, Università degli Studi di Milano, Milan, Italy; ‡Neoplastic Progression Unit, Department of Experimental Oncology, IRCCS Istituto Nazionale Tumori "Fondazione G. Pascale," Naples, Italy; §SUN, Second University of Naples, Naples, Italy; ‖Department of Pharmacy, University Federico II, Naples, Italy; and ¶Hunimed-Humanitas University, Milan, Italy.
Background:
Leukocyte migration across the blood barrier and into tissues represents a key process in the pathogenesis of inflammatory bowel diseases. The urokinase receptor (urokinase-type plasminogen activator receptor) is a master regulator of leukocyte recruitment. We recently found that cyclization of the urokinase-type plasminogen activator receptor-derived peptide Ser-Arg-Ser-Arg-Tyr [SRSRY] inhibits transendothelial migration of monocytes. Now, we have explored the effects of [SRSRY] administration during experimental colitis.
Methods:
The effects of [SRSRY] on cytokine profile, cytoskeletal organization, and cell migration were investigated using phorbol-12-myristate acetate-differentiated THP-1 cells exposed to polarizing stimuli. In vivo, [SRSRY] was intraperitoneally administered during dextran sodium sulfate- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis in wild-type or urokinase-type plasminogen activator receptor knockout mice. Levels of pro-inflammatory cytokines and inflammatory monocytes in mucosal infiltrates were assessed by enzyme-linked immunosorbent assay and flow cytometry, respectively.
Results:
[SRSRY] prevents M0 to M1 transition and migration of M1 polarized macrophages. In vivo, [SRSRY] reduces intestinal inflammation diminishing body weight loss and disease activity index. These beneficial effects are accompanied by a reduction of interleukin 1β, interleukin 6, and tumor necrosis factor α, an increase of interleukin 10, and an abridged recruitment of inflammatory monocytes to the inflamed tissue.
Conclusions:
Altogether, these findings indicate that [SRSRY] may be considered as a new drug useful for the pharmacological treatment of chronic inflammatory diseases, such as inflammatory bowel diseases.
