Pannexin 1 channels regulate leukocyte emigration through the venous endothelium during acute inflammation

Alexander W. Lohman, Igor L. Leskov, Joshua T. Butcher, Scott R. Johnstone, Tara A. Stokes, Daniela Begandt, Leon J. DeLalio, Angela K. Best, Silvia Penuela, Norbert Leitinger, Kodi S. Ravichandran, Karen Y. Stokes and Brant E. Isakson ()
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Alexander W. Lohman: University of Virginia School of Medicine
Igor L. Leskov: Louisiana State University Health Sciences Center
Joshua T. Butcher: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine
Scott R. Johnstone: British Heart Foundation Cardiovascular Research Centre, College of Medical, Veterinary and Life Sciences, University of Glasgow
Tara A. Stokes: Louisiana State University Health Sciences Center
Daniela Begandt: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine
Leon J. DeLalio: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine
Angela K. Best: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine
Silvia Penuela: University of Western Ontario
Norbert Leitinger: University of Virginia School of Medicine
Kodi S. Ravichandran: Immunology and Cancer Biology, University of Virginia School of Medicine
Karen Y. Stokes: Louisiana State University Health Sciences Center
Brant E. Isakson: University of Virginia School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8965

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