TNFα promotes CAR-dependent migration of leukocytes across epithelial monolayers

Penny E. Morton; Alexander Hicks; Elena Ortiz-Zapater; Swetavalli Raghavan; Rosemary Pike; Alistair Noble; Abigail Woodfin; Gisli Jenkins; Emma Rayner; George Santis; Maddy Parsons

doi:10.1038/srep26321

TNFα promotes CAR-dependent migration of leukocytes across epithelial monolayers

Penny E. Morton, Alexander Hicks, Elena Ortiz-Zapater, Swetavalli Raghavan, Rosemary Pike, Alistair Noble, Abigail Woodfin, Gisli Jenkins, Emma Rayner, George Santis, Maddy Parsons^*

^*Corresponding author for this work

Research & Technical Staff

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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-PKĆ 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.

Original language	English
Article number	26321
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep26321
Publication status	Published - 19 May 2016

Bibliographical note

Funding Information:
This study was funded by the Medical Research Council (MRC) UK, Biotechnology and Biological Sciences Research Council (BBSRC), Royal Society, National Institute for Health Research (NIHR) Clinical Research Facility and NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust, King's College London.

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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-PK{\'C} 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.",

author = "Morton, {Penny E.} and Alexander Hicks and Elena Ortiz-Zapater and Swetavalli Raghavan and Rosemary Pike and Alistair Noble and Abigail Woodfin and Gisli Jenkins and Emma Rayner and George Santis and Maddy Parsons",

note = "Funding Information: This study was funded by the Medical Research Council (MRC) UK, Biotechnology and Biological Sciences Research Council (BBSRC), Royal Society, National Institute for Health Research (NIHR) Clinical Research Facility and NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust, King's College London.",

year = "2016",

month = may,

day = "19",

doi = "10.1038/srep26321",

language = "English",

volume = "6",

journal = "Scientific Reports",

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T1 - TNFα promotes CAR-dependent migration of leukocytes across epithelial monolayers

AU - Morton, Penny E.

AU - Hicks, Alexander

AU - Ortiz-Zapater, Elena

AU - Raghavan, Swetavalli

AU - Pike, Rosemary

AU - Noble, Alistair

AU - Woodfin, Abigail

AU - Jenkins, Gisli

AU - Rayner, Emma

AU - Santis, George

AU - Parsons, Maddy

N1 - Funding Information: This study was funded by the Medical Research Council (MRC) UK, Biotechnology and Biological Sciences Research Council (BBSRC), Royal Society, National Institute for Health Research (NIHR) Clinical Research Facility and NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust, King's College London.

PY - 2016/5/19

Y1 - 2016/5/19

N2 - 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-PKĆ 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.

AB - 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-PKĆ 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.

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U2 - 10.1038/srep26321

DO - 10.1038/srep26321

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AN - SCOPUS:84970038541

SN - 2045-2322

VL - 6

JO - Scientific Reports

JF - Scientific Reports

M1 - 26321

ER -

TNFα promotes CAR-dependent migration of leukocytes across epithelial monolayers

Abstract

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