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Negative regulation of epithelium-neutrophil interactions via activation of CD44
M Si-Tahar1, S Sitaraman, T Shibahara
1Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA. msitahar@pasteur.fr
Abstract:
Polymorphonuclear neutrophil (PMN) migration across epithelia is a common feature of active inflammation. Given the suggested role of carbohydrates in this process, we examined the receptor CD44. The standard CD44 isoform was expressed at the cell surface of PMN. PMN migration across model polarized intestinal epithelia was reduced (by 60%) if the CD44 receptor was activated by either a specific antibody (clone IM7) or the natural soluble ligand, hyaluronic acid. This inhibitory effect following receptor activation occurred with both basolateral-to-apical- and apical-to-basolateral-directed migration. The anti-CD44 antibody similarly reduced PMN migration through filters in the absence of epithelia, while preincubation of the antibody with the epithelium did not alter subsequent PMN transepithelial migration. These data suggest that PMN, rather than epithelial, CD44 is responsible for these effects. A similar inhibitory effect of anti-CD44 antibody was also observed on migration of intraepithelial lymphocytes. The molecular mechanism involved in such negative signaling following CD44 activation may include modulation of outside-in cell signaling. While neither the anti-CD44 antibody nor CD44 ligand affected PMN mobilization of intracellular Ca(2+), both led to increased adenylate cyclase activity, an inhibitory signal for PMN migration. Together, these results suggest that CD44 of PMN may potentially serve as a negative regulator of leukocyte migration across biological surfaces such as columnar epithelia.
Insights
Activating the CD44 receptor on polymorphonuclear neutrophils (PMN) significantly reduces their migration across epithelia. This suggests CD44 acts as a negative regulator of leukocyte movement during inflammation.
Area of Science:
- Immunology
- Cell Biology
- Inflammation Research
Background:
- Polymorphonuclear neutrophil (PMN) migration is crucial in active inflammation.
- The role of carbohydrates in leukocyte migration is under investigation.
- CD44 is a cell surface receptor implicated in cell adhesion and migration.
Purpose of the Study:
- To investigate the role of the CD44 receptor in PMN migration across polarized intestinal epithelia.
- To determine if CD44 activation inhibits or promotes PMN transepithelial migration.
- To elucidate the molecular mechanisms underlying CD44-mediated regulation of leukocyte migration.
Main Methods:
- Utilized model polarized intestinal epithelia to study PMN migration.
- Activated the CD44 receptor using a specific antibody (clone IM7) and its natural ligand, hyaluronic acid.
- Assessed PMN migration in both basolateral-to-apical and apical-to-basolateral directions.
- Measured intracellular Ca(2+) mobilization and adenylate cyclase activity in PMNs.
Main Results:
- Activation of PMN CD44 by antibody or hyaluronic acid reduced migration across epithelia by 60%.
- This inhibitory effect was observed in both directions of migration and also on intraepithelial lymphocytes.
- CD44 activation increased adenylate cyclase activity, an inhibitory signal for PMN migration, without affecting intracellular Ca(2+).
Conclusions:
- PMN CD44, rather than epithelial CD44, is responsible for the observed inhibitory effects on migration.
- CD44 activation on PMNs acts as a negative regulator of leukocyte migration across epithelial barriers.
- The findings suggest CD44 signaling modulates adenylate cyclase activity, impacting leukocyte trafficking in inflammation.