1. Pannexin 1 channels regulate leukocyte emigration through the venous endothelium during acute inflammation.
- Author
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Lohman AW, Leskov IL, Butcher JT, Johnstone SR, Stokes TA, Begandt D, DeLalio LJ, Best AK, Penuela S, Leitinger N, Ravichandran KS, Stokes KY, and Isakson BE
- Subjects
- Adenosine Triphosphate metabolism, Animals, Cell Adhesion, Cells, Cultured, Endothelium, Vascular immunology, Human Umbilical Vein Endothelial Cells, Humans, Male, Mice, Inbred C57BL, Phosphorylation, Tumor Necrosis Factor-alpha metabolism, Up-Regulation, Venules immunology, src-Family Kinases metabolism, Connexins metabolism, Endothelial Cells metabolism, Inflammation metabolism, Leukocytes physiology, Nerve Tissue Proteins metabolism, Transendothelial and Transepithelial Migration
- Abstract
Inflammatory cell recruitment to local sites of tissue injury and/or infection is controlled by a plethora of signalling processes influencing cell-to-cell interactions between the vascular endothelial cells (ECs) in post-capillary venules and circulating leukocytes. Recently, ATP-sensitive P2Y purinergic receptors have emerged as downstream regulators of EC activation in vascular inflammation. However, the mechanism(s) regulating cellular ATP release in this response remains elusive. Here we report that the ATP-release channel Pannexin1 (Panx1) opens downstream of EC activation by TNF-α. This process involves activation of type-1 TNF receptors, recruitment of Src family kinases (SFK) and SFK-dependent phosphorylation of Panx1. Using an inducible, EC-specific Panx1 knockout mouse line, we report a previously unidentified role for Panx1 channels in promoting leukocyte adhesion and emigration through the venous wall during acute systemic inflammation, placing Panx1 channels at the centre of cytokine crosstalk with purinergic signalling in the endothelium.
- Published
- 2015
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