Blockade of PSGL-1 attenuates CD14+ monocytic cell recruitment in intestinal mucosa and ameliorates ileitis in SAMP1/Yit mice

Abstract

The pathogenesis of Crohn's disease (CD) is not known. However, monocytes and macrophages are thought to play important roles in the development of mucosal inflammation. Therefore, in this study, we examined the role of monocyte-endothelial cell interactions in senescence-accelerated mouse P1 (SAMP1)/Yit mice, a murine model of spontaneous ileitis. Fluorescence-labeled CD14+ monocytic cells isolated from the spleen and mesenteric lymph nodes of AKR/J (control) mice were injected into the tail veins of recipient (AKR/J and SAMP1/Yit) mice, and migration in the postcapillary venules (PCV) of Peyer's patches, submucosal venules, and villus microvessels of the terminal ileum was monitored by using an intravital microscope. Rolling and adhesion of CD14+ monocytic cells in the PCV of Peyer's patches and microvessels of the terminal ileum were increased in SAMP1/Yit mice. An immunohistochemical study showed increased expression of P-selectin glycoprotein-1 (PSGL-1), P-selectin, and vascular cell adhesion molecule-1 in the terminal ileum of SAMP1/Yit mice. Antibodies against these three adhesion molecules significantly inhibited adhesion of CD14+ monocytic cells to the PCV of Peyer's patches and microvessels of the terminal ileum, treatment with an anti-PSGL-1 monoclonal antibody (mAb) showing the strongest suppressive effect. Anti-PSGL-1 mAb also attenuated T cell adhesion in microvessels of intestinal mucosa. In addition, periodical administration of an anti-PSGL-1 mAb for 7 weeks significantly ameliorated ileitis of SAMP1/Yit mice. The results suggest that PSGL-1-P-selectin interaction plays an important role in monocyte-endothelial cell interactions and the development of ileitis in a murine model of CD and that the blockade of this adhesion molecule may be a novel strategy for treating CD.

Functional Role of P-Selectin Glycoprotein Ligand 1/P-Selectin Interaction in the Generation of Tolerogenic Dendritic Cells

“…We consider that our findings will contribute to further understand the physiological role of PSGL-1 in the immune system, and the complexity of the different stimuli for the induction of immune tolerance. In addition, our findings may have practical relevance because it has been proposed that PSGL-1 is a potential target for the therapy of autoimmune and inflammatory diseases (41,52,53).…”

Ly6Chigh Monocytes Control Cerebral Toxoplasmosis

“…However, the authors speculated that other adhesion molecules such as LFA-1 and VCAM-1 (ligand VLA-4) may not be key factors in monocyte homing, as their ligands were expressed at lower levels on Ly6C high cells. Furthermore, other studies detected PSGL-1-dependent monocyte migration in the periphery during Leishmania major infection, tumor metastasis, and thrombus formation (48,81,82). Thus, to our knowledge, we investigated for the first time PSGL-1-dependent monocyte recruitment to the CNS.…”

“…The dependence on PSGL-1 for lymphocyte migration is well established (56,57,(79)(80)(81)(82). However, to date, the function of PSGL-1 in monocyte recruitment has not been sufficiently addressed.…”

P-selectin glycoprotein ligand-1 deficiency is protective against obesity-related insulin resistance

“…In the model of cold ischemia/ reperfusion, hepatic endothelial neutrophil infiltration and hepatocyte injury were diminished, and the expression of TNF-␣, IL-6, iNOS, IL-2, and IFN-␥ mRNA was decreased in livers pretreated with recombinant PSGL-Ig (36). Other reports showed that blockade of PSGL-1 attenuated macrophage recruitment in intestinal mucosa and ameliorated ileitis in a mouse model of Crohn's disease (37,38).…”