Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep26321
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Funding
- Medical Research Council (MRC) UK
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Royal Society
- National Institute for Health Research (NIHR) Clinical Research Facility
- NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust, King's College London
- MRC [MR/K002597/1] Funding Source: UKRI
- Medical Research Council [MR/K002597/1] Funding Source: researchfish
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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 TNF alpha acts in a paracrine manner on epithelial cells via a TNFR1-PI3K-PKC delta 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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