title: Leukocyte-borne α(1,3)-fucose is a negative regulator of β2-integrin-dependent recruitment in lung inflammation.
abstract: Leukocyte recruitment in inflammation is a multistep, sequential cascade where the initial step is the selectin-dependent tethering, followed by the formation of firmer integrin-mediated adhesive forces leading to extravasation. The α(1,3)-fucose-containing sialyl-Lewis X (sLeX) is the archetypical ligand on leukocyte surfaces mediating selectin interactions. Canonically, disruption of α(1,3)-fucose formation ablates selectin-mediated adhesion, dramatically reducing trafficking. We report a paradoxical response to α(1,3)-fucose deficiency in which the loss exacerbated rather than attenuated leukocyte recruitment in a murine model of acute airway inflammation. The architecture of the capillary-dominated vasculature in the lung minimized the importance of the selectin dependent step, and we observed that α(1,3)-fucose deficiency augmented CXCR2-mediated Rap1-GTP signaling to enhance the β2-integrin-ICAM-1-binding axis. The data disclose a previously unknown function for α(1,3)-fucose, in which this structure negatively regulates the integrin activation step in leukocyte recruitment.
authors: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA.|Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, New York, USA.
authors: Alexander
authors: A
authors: Buffone
authors: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors: Mehrab
authors: M
authors: Nasirikenari
authors: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors: Charles T
authors: CT
authors: Manhardt
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors: Amit
authors: A
authors: Lugade
authors: Department of Pathology, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors: Paul N
authors: PN
authors: Bogner
authors: Department of Dermatology Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and.|Program of Excellence in Glycosciences, Harvard Medical School, Boston, Massachusetts, USA.
authors: Robert
authors: R
authors: Sackstein
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors: Yasmin
authors: Y
authors: Thanavala
authors: Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, New York, USA.
authors: Sriram
authors: S
authors: Neelamegham
authors: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA; joseph.lau@roswellpark.org.
authors: Joseph T Y
authors: JT
authors: Lau
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000378:metabolism*; D002448:Cell Adhesion; D002450:Cell Communication; D004195:Disease Models, Animal; D005643:Fucose / Q000378:metabolism*; D005647:Fucosyltransferases / Q000172:deficiency / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism*; D008024:Ligands; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D010537:Peritoneum / Q000473:pathology; D011014:Pneumonia / Q000378:metabolism* / Q000473:pathology*; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D019087:Selectins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018821:CD18 Antigens; D008024:Ligands; D023063:Receptors, Interleukin-8B; D019087:Selectins; D018799:Intercellular Adhesion Molecule-1; D005643:Fucose; D005647:Fucosyltransferases; D019158:N-Acetylneuraminic Acid
keywords: CXCR2; ICAM-1; NTHI; fucosyltransferase; neutrophil