Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 178, Issue 5, Pages 2437-2446Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2011.01.039
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Funding
- American Heart Association
- U.S. National Institutes of Health [R01 HL69438, 0735165N]
- Raman y Cajal
- Spanish Ministry of Science and Innovation [SAF2009-11037]
- FP7-People-IRG Program [246655]
- Spanish Ministry of Science and Innovation
- Pro-CNIC Foundation
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Endothelial selectins guide the migration of inflammatory T cells to extralymphoid tissues. Whereas P-selectin glycoprotein ligand-1 (PSGL-1) functions as the exclusive ligand for P-selectin, it acts in coordination with additional glycoproteins to mediate E-selectin binding. CD44 can act as one such ligand in neutrophils, but its contribution in inflammatory T lymphocytes remains unexplored. We have used real-time in vivo imaging of the cremasteric and dermal microcirculations to explore the dynamics of leukocyte recruitment, as well as the physiological contribution of CD44 in a model of Th1-driven inflammation. CD4(+) T-cell rolling frequency and kinetics, as well as arrest, were dependent on endothelial selectins and were markedly altered under inflammatory conditions. CD44 extracted from Th1 cells bound to soluble E-selectin in vitro and cooperated with PSGL-1 by controlling rolling velocities and promoting firm arrest. Using several competitive recruitment assays in a delayed-type hypersensitivity model, we show that the combined absence of CD44 and PSGL-1 impairs inflammatory T-cell recruitment beyond that of PSGL-1 alone. Differential expression of leukocyte fucosyltransferases in these cells may account for the differential use of E-selectin ligands relative to neutrophils. Our results identify additional mechanisms by which CD44 modulates the inflammatory response. (Am J Pathol 2011, 78:2437-2446; DOI: 10.1016/j.ajpath.2011.01.039)
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