title: The PSGL-1-L-selectin signaling complex regulates neutrophil adhesion under flow.
abstract: Neutrophils are recruited from the blood to sites of inflammation, where they contribute to immune defense but may also cause tissue damage. During inflammation, neutrophils roll along the microvascular endothelium before arresting and transmigrating. Arrest requires conformational activation of the integrin lymphocyte function-associated antigen 1 (LFA-1), which can be induced by selectin engagement. Here, we demonstrate that a subset of P-selectin glycoprotein ligand-1 (PSGL-1) molecules is constitutively associated with L-selectin. Although this association does not require the known lectin-like interaction between L-selectin and PSGL-1, the signaling output is dependent on this interaction and the cytoplasmic tail of L-selectin. The PSGL-1-L-selectin complex signals through Src family kinases, ITAM domain-containing adaptor proteins, and other kinases to ultimately result in LFA-1 activation. The PSGL-1-L-selectin complex-induced signaling effects on neutrophil slow rolling and recruitment in vivo demonstrate the functional importance of this pathway. We conclude that this is a signaling complex specialized for sensing adhesion under flow.
authors.affiliation: Department of Anesthesiology, Intensive Care, and Pain Medicine; and 2 Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation; University of Münster, 48149 Münster, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Stadtmann
authors.forename: Giulia
authors.initials: G
authors.lastname: Germena
authors.forename: Helena
authors.initials: H
authors.lastname: Block
authors.forename: Mark
authors.initials: M
authors.lastname: Boras
authors.forename: Jan
authors.initials: J
authors.lastname: Rossaint
authors.forename: Prithu
authors.initials: P
authors.lastname: Sundd
authors.forename: Craig
authors.initials: C
authors.lastname: Lefort
authors.forename: Charles I
authors.initials: CI
authors.lastname: Fisher
authors.forename: Konrad
authors.initials: K
authors.lastname: Buscher
authors.forename: Bernadette
authors.initials: B
authors.lastname: Gelschefarth
authors.forename: Ana
authors.initials: A
authors.lastname: Urzainqui
authors.forename: Volker
authors.initials: V
authors.lastname: Gerke
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D019041:L-Selectin / Q000378:metabolism*; D036904:Leukocyte Rolling; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D012212:Rheology; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D019041:L-Selectin; D019061:src-Family Kinases