title: TNFα promotes CAR-dependent migration of leukocytes across epithelial monolayers.
abstract: Trans-epithelial migration (TEpM) of leukocytes during inflammation requires engagement with receptors expressed on the basolateral surface of the epithelium. One such receptor is Coxsackie and Adenovirus Receptor (CAR) that binds to Junctional Adhesion Molecule-like (JAM-L) expressed on leukocytes. Here we provide the first evidence that efficient TEpM of monocyte-derived THP-1 cells requires and is controlled by phosphorylation of CAR. We show that TNFα acts in a paracrine manner on epithelial cells via a TNFR1-PI3K-PKCδ pathway leading to CAR phosphorylation and subsequent transmigration across cell junctions. Moreover, we show that CAR is hyper-phosphorylated in vivo in acute and chronic lung inflammation models and this response is required to facilitate immune cell recruitment. This represents a novel mechanism of feedback between leukocytes and epithelial cells during TEpM and may be important in controlling responses to pro-inflammatory cytokines in pathological settings.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guys Campus, London, SE1 1UL, UK.
authors.forename: Penny E
authors.initials: PE
authors.lastname: Morton
authors.affiliation: Division of Asthma, Allergy &Lung Biology, King's College London, 5th Floor Tower Wing, Guy's Hospital Campus, London, SE1 1UL, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hicks
authors.affiliation: Division of Asthma, Allergy &Lung Biology, King's College London, 5th Floor Tower Wing, Guy's Hospital Campus, London, SE1 1UL, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Ortiz-Zapater
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guys Campus, London, SE1 1UL, UK.
authors.forename: Swetavalli
authors.initials: S
authors.lastname: Raghavan
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guys Campus, London, SE1 1UL, UK.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Pike
authors.affiliation: Division of Asthma, Allergy &Lung Biology, King's College London, 5th Floor Tower Wing, Guy's Hospital Campus, London, SE1 1UL, UK.
authors.forename: Alistair
authors.initials: A
authors.lastname: Noble
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, EC1M 6BQ, UK.
authors.forename: Abigail
authors.initials: A
authors.lastname: Woodfin
authors.affiliation: Respiratory Research Unit, University of Nottingham, Clinical Sciences Building, City Campus, Nottingham, NG5 1PB, UK.
authors.forename: Gisli
authors.initials: G
authors.lastname: Jenkins
authors.affiliation: Public Health England, Salisbury, Wiltshire, SP4 0JG, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Rayner
authors.affiliation: Division of Asthma, Allergy &Lung Biology, King's College London, 5th Floor Tower Wing, Guy's Hospital Campus, London, SE1 1UL, UK.
authors.forename: George
authors.initials: G
authors.lastname: Santis
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guys Campus, London, SE1 1UL, UK.
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
mesh_terms: D000818:Animals; D002450:Cell Communication; D002461:Cell Line, Transformed; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007365:Intercellular Junctions / Q000502:physiology; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D011014:Pneumonia; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D014409:Tumor Necrosis Factor-alpha