title: Chemorepellent Semaphorin 3E Negatively Regulates Neutrophil Migration In Vitro and In Vivo.
abstract: Neutrophil migration is an essential step in leukocyte trafficking during inflammatory responses. Semaphorins, originally discovered as axon guidance cues in neural development, have been shown to regulate cell migration beyond the nervous system. However, the potential contribution of semaphorins in the regulation of neutrophil migration is not well understood. This study examines the possible role of a secreted chemorepellent, Semaphorin 3E (Sema3E), in neutrophil migration. In this study, we demonstrated that human neutrophils constitutively express Sema3E high-affinity receptor, PlexinD1. Sema3E displayed a potent ability to inhibit CXCL8/IL-8-induced neutrophil migration as determined using a microfluidic device coupled to real-time microscopy and a transwell system in vitro. The antimigratory effect of Sema3E on human neutrophil migration was associated with suppression of CXCL8/IL-8-mediated Ras-related C3 botulinum toxin substrate 1 GTPase activity and actin polymerization. We further addressed the regulatory role of Sema3E in the regulation of neutrophil migration in vivo. Allergen airway exposure induced higher neutrophil recruitment into the lungs of Sema3e-/-mice compared with wild-type controls. Administration of exogenous recombinant Sema3E markedly reduced allergen-induced neutrophil recruitment into the lungs, which was associated with alleviation of allergic airway inflammation and improvement of lung function. Our data suggest that Sema3E could be considered an essential regulatory mediator involved in modulation of neutrophil migration throughout the course of neutrophilic inflammation.
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
authors.forename: Hesam
authors.initials: H
authors.lastname: Movassagh
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
authors.forename: Abeer
authors.initials: A
authors.lastname: Saati
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.|Department of Physics and Astronomy, Faculty of Science, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada.
authors.forename: Saravanan
authors.identifier: 0000-0002-1787-3356
authors.initials: S
authors.lastname: Nandagopal
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
authors.forename: Ashfaque
authors.initials: A
authors.lastname: Mohammed
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
authors.forename: Nazanin
authors.identifier: 0000-0001-8403-0175
authors.initials: N
authors.lastname: Tatari
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
authors.forename: Lianyu
authors.initials: L
authors.lastname: Shan
authors.affiliation: Department of Medical Oncology, Laboratory of Immunobiology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02215; and.
authors.forename: Jonathan S
authors.identifier: 0000-0002-9478-9609
authors.initials: JS
authors.lastname: Duke-Cohan
authors.affiliation: Department of Medical Microbiology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Fowke
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.|Department of Physics and Astronomy, Faculty of Science, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada; abdel.gounni@umanitoba.ca.
authors.forename: Abdelilah S
authors.identifier: 0000-0003-1265-6560
authors.initials: AS
authors.lastname: Gounni
mesh_terms: D000199:Actins / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000032:analysis; D002465:Cell Movement; D002634:Chemotaxis, Leukocyte; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D056656:Lab-On-A-Chip Devices; D008562:Membrane Glycoproteins; D009504:Neutrophils / Q000502:physiology*; D039961:Semaphorins / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; C508606:CXCL8 protein, human; D015816:Cell Adhesion Molecules, Neuronal; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C493082:PLXND1 protein, human; C107953:RAC1 protein, human; C494123:SEMA3E protein, human; D039961:Semaphorins; D020830:rac1 GTP-Binding Protein