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TRPV4 Protects the Lung from Bacterial Pneumonia via MAPK Molecular Pathway Switching

Rachel G. Scheraga, Susamma Abraham, Lisa M. Grove, Brian D. Southern, James F. Crish, Apostolos Perelas, Christine McDonald, Kewal Asosingh, Jeffrey D. Hasday and Mitchell A. Olman
J Immunol January 22, 2020, ji1901033; DOI: https://doi.org/10.4049/jimmunol.1901033
Rachel G. Scheraga
*Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195;
†Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and
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Susamma Abraham
†Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and
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Lisa M. Grove
†Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and
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Brian D. Southern
*Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195;
†Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and
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James F. Crish
†Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and
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Apostolos Perelas
*Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195;
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Christine McDonald
†Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and
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Kewal Asosingh
†Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and
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Jeffrey D. Hasday
‡Department of Pulmonary and Critical Care, University of Maryland, Baltimore, MD 21201
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Mitchell A. Olman
*Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195;
†Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and
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Key Points

  • TRPV4 mediates the host defense and lung injury response to bacterial pneumonia.

  • TRPV4 mediates these effects through MAPK switching from JNK to p38 through DUSP1.

Abstract

Mechanical cell–matrix interactions can drive the innate immune responses to infection; however, the molecular underpinnings of these responses remain elusive. This study was undertaken to understand the molecular mechanism by which the mechanosensitive cation channel, transient receptor potential vanilloid 4 (TRPV4), alters the in vivo response to lung infection. For the first time, to our knowledge, we show that TRPV4 protects the lung from injury upon intratracheal Pseudomonas aeruginosa in mice. TRPV4 functions to enhance macrophage bacterial clearance and downregulate proinflammatory cytokine secretion. TRPV4 mediates these effects through a novel mechanism of molecular switching of LPS signaling from predominant activation of the MAPK, JNK, to that of p38. This is accomplished through the activation of the master regulator of inflammation, dual-specificity phosphatase 1. Further, TRPV4’s modulation of the LPS signal is mechanosensitive in that both upstream activation of p38 and its downstream biological consequences depend on pathophysiological range extracellular matrix stiffness. We further show the importance of TRPV4 on LPS-induced activation of macrophages from healthy human controls. These data are the first, to our knowledge, to demonstrate new roles for macrophage TRPV4 in regulating innate immunity in a mechanosensitive manner through the modulation of dual-specificity phosphatase 1 expression to mediate MAPK activation switching.

Footnotes

  • This work was supported by National Institutes of Health (NIH) Grants HL133380 (to R.G.S.), HL132079 (to B.D.S.), and HL-133721 and HL-119792 (to M.A.O.). This publication was made possible by the Clinical and Translational Science Collaborative of Cleveland (Award UL1TR000439), the National Center for Advancing Translational Sciences component of the NIH, and the NIH Roadmap for Medical Research (to R.G.S.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. This work utilized the Leica SP8 confocal microscope that was purchased with funding from NIH Shared Instrumentation Grant 1S10OD019972-01.

  • The online version of this article contains supplemental material.

  • Received August 23, 2019.
  • Accepted December 22, 2019.
  • Copyright © 2020 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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TRPV4 Protects the Lung from Bacterial Pneumonia via MAPK Molecular Pathway Switching
Rachel G. Scheraga, Susamma Abraham, Lisa M. Grove, Brian D. Southern, James F. Crish, Apostolos Perelas, Christine McDonald, Kewal Asosingh, Jeffrey D. Hasday, Mitchell A. Olman
The Journal of Immunology January 22, 2020, ji1901033; DOI: 10.4049/jimmunol.1901033

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TRPV4 Protects the Lung from Bacterial Pneumonia via MAPK Molecular Pathway Switching
Rachel G. Scheraga, Susamma Abraham, Lisa M. Grove, Brian D. Southern, James F. Crish, Apostolos Perelas, Christine McDonald, Kewal Asosingh, Jeffrey D. Hasday, Mitchell A. Olman
The Journal of Immunology January 22, 2020, ji1901033; DOI: 10.4049/jimmunol.1901033
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Print ISSN 0022-1767        Online ISSN 1550-6606