The urokinase plasminogen activator receptor (uPAR) controls macrophage phagocytosis in intestinal inflammation.
OBJECTIVE
Inflammation plays crucial roles in the pathogenesis of several chronic inflammatory disorders, including Crohn's disease (CD) and UC, the two major forms of IBD. The urokinase plasminogen activator receptor (uPAR) exerts pleiotropic functions over the course of both physiological and pathological processes. uPAR not only has a key role in fibrinolysis but also modulates the development of protective immunity. Additionally, uPAR supports extracellular matrix degradation and regulates cell migration, adhesion and proliferation, thus influencing the development of inflammatory and immune responses. This study aimed to evaluate the role of uPAR in the pathogenesis of IBD.


METHODS
The functional role of uPAR was assessed in established experimental models of colitis. uPAR deficiency effects on cytokine release, polarisation and bacterial phagocytosis were analysed in colonic macrophages. uPAR expression was analysed in surgical specimens collected from normal subjects and patients with IBD.


RESULTS
In mice, uPAR expression is positively regulated as colitis progresses. uPAR-KO mice displayed severe inflammation compared with wild-type littermates, as indicated by clinical assessment, endoscopy and colon histology. The absence of uPAR led to an increased production of inflammatory cytokines by macrophages that showed an M1 polarisation and impaired phagocytosis. In human IBD, CD68(+) macrophages derived from the inflamed mucosa expressed low levels of uPAR.


CONCLUSIONS
These findings point to uPAR as an essential component of intestinal macrophage functions and unravel a new potential target to control mucosal inflammation in IBD.
IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy Department of Translational Medicine, University of Milan, Milan, Italy.
Marco
M
Genua
IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy.
Silvia
S
D'Alessio
IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy.
Javier
J
Cibella
IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy.
Alessandro
A
Gandelli
IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy.
Emanuela
E
Sala
IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy.
Carmen
C
Correale
Department of Translational Medicine, University of Milan, Milan, Italy Department of Surgery-IBD Surgery Unit, Humanitas Clinical and Research Center, Rozzano, Italy.
Antonino
A
Spinelli
Department of Pediatric Hematology/Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
Vincenzo
V
Arena
IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy Department of Translational Medicine, University of Milan, Milan, Italy.
Alberto
A
Malesci
Department of Pediatric Hematology/Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
Sergio
S
Rutella
W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, USA.
Victoria A
VA
Ploplis
IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy.
Stefania
S
Vetrano
IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy.
Silvio
S
Danese
D000818:Animals; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator / Q000502:physiology*
D055293:Receptors, Urokinase Plasminogen Activator
Bacterial Translocation; Experimental Colitis; Integrins; Macrophages; Molecular Mechanisms