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UDP-glucose promotes neutrophil recruitment in the lung

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Abstract

In addition to their role in glycosylation reactions, UDP-sugars are released from cells and activate widely distributed cell surface P2Y14 receptors (P2Y14R). However, the physiological/pathophysiological consequences of UDP-sugar release are incompletely defined. Here, we report that UDP-glucose levels are abnormally elevated in lung secretions from patients with cystic fibrosis (CF) as well as in a mouse model of CF-like disease, the βENaC transgenic (Tg) mouse. Instillation of UDP-glucose into wild-type mouse tracheas resulted in enhanced neutrophil lung recruitment, and this effect was nearly abolished when UDP-glucose was co-instilled with the P2Y14R antagonist PPTN [4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl-2-naphthoic acid]. Importantly, administration of PPTN to βENaC-Tg mice reduced neutrophil lung inflammation. These results suggest that UDP-glucose released into the airways acts as a local mediator of neutrophil inflammation.

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Acknowledgments

The authors are grateful to Dr. Silvia Kreda and Dr. Michael Chua (Histology/Microscopy Core) for the use of the Nikon Nicrophot-SA microscopy, Dr. Wanda O’Neal and Kristen Wilkinson (Mouse Core) for assisting with the βENaC-Tg mouse studies, and to Catharina van Heusden for technical assistance with the use of the HPLC.

This work was supported by the National Institutes of Health (NIH) National Institute of General Medical Sciences [R01-GM38213] (TKH), the NIH National Heart, Lung, and Blood Institute [P01-HL110873] (ERL), the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program (KAJ), the NIH Specialized Centers of Clinically Orientated Research [P50-HL084934] (SD), the US EPA cooperative agreement CR 833463015-35475 and NHLBI-RO1 HL080337 (NEA), and the American Cystic Fibrosis Foundation [SESMA1510] and North Carolina Translational & Clinical Science [NCTraCS 550KR101513] (JIS). The Histology/Microscopy and Mouse Cores were supported by NIH P30-DK065988.

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Authors and Affiliations

  1. Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina School of Medicine, 6007 Thurston-Bowles Building, CB 7248, Chapel Hill, NC, 27599-7248, USA

    Juliana I. Sesma, Alessandra Livraghi-Butrico, Hong Dang, Scott Donaldson & Eduardo R. Lazarowski

  2. Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Clarissa D. Weitzer & T. Kendall Harden

  3. Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Neil E. Alexis

  4. Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Kenneth A. Jacobson

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  1. Juliana I. Sesma
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  2. Clarissa D. Weitzer
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  3. Alessandra Livraghi-Butrico
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  4. Hong Dang
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  5. Scott Donaldson
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  7. Kenneth A. Jacobson
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  8. T. Kendall Harden
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  9. Eduardo R. Lazarowski
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Correspondence to Eduardo R. Lazarowski.

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All subjects were studied at the University of North Carolina at Chapel Hill (Chapel Hill, NC, USA), and studies were approved by the Institutional Review Board. Animal protocols were reviewed and approved by the Institutional Animal Care and Use Committee of the University of North Carolina at Chapel Hill.

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Sesma, J.I., Weitzer, C.D., Livraghi-Butrico, A. et al. UDP-glucose promotes neutrophil recruitment in the lung. Purinergic Signalling 12, 627–635 (2016). https://doi.org/10.1007/s11302-016-9524-5

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