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IL-36γ Is a Key Regulator of Neutrophil Infiltration in the Vaginal Microenvironment and Limits Neuroinvasion in Genital HSV-2 Infection

Jameson K. Gardner, Alison Swaims-Kohlmeier and Melissa M. Herbst-Kralovetz
J Immunol October 2, 2019, ji1900280; DOI: https://doi.org/10.4049/jimmunol.1900280
Jameson K. Gardner
*Department of Basic Medical Sciences, University of Arizona College of Medicine–Phoenix, Phoenix, AZ 85004;
†Molecular and Cellular Biology Graduate Program, School of Life Sciences, Arizona State University, Tempe, AZ 85287;
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Alison Swaims-Kohlmeier
‡Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333; and
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Melissa M. Herbst-Kralovetz
*Department of Basic Medical Sciences, University of Arizona College of Medicine–Phoenix, Phoenix, AZ 85004;
§Department of Obstetrics and Gynecology, University of Arizona College of Medicine–Phoenix, Phoenix, AZ 85004
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Key Points

  • IL-36γ is crucial for neutrophil recruitment in response to genital HSV-2 infection.

  • Genital HSV-2 disease pathogenesis progresses more rapidly in IL-36γ−/− mice.

  • IL-36γ−/− mice exhibit significantly increased HSV-2 neuroinvasion and virus spread.

Abstract

HSV-2 is a neurotropic virus that causes a persistent, lifelong infection that increases risk for other sexually transmitted infections. The vaginal epithelium is the first line of defense against HSV-2 and coordinates the immune response through the secretion of immune mediators, including the proinflammatory cytokine IL-36γ. Previously, we showed that IL-36γ treatment promoted transient polymorphonuclear cell infiltration to the vaginal cavity and protected against lethal HSV-2 challenge. In this report, we reveal that IL-36γ specifically induces transient neutrophil infiltration but does not impact monocyte and macrophage recruitment. Using IL-36γ−/− mice in a lethal HSV-2 challenge model, we show that neutrophil counts are significantly reduced at 1 and 2 d postinfection and that KC-mediated mature neutrophil recruitment is impaired in IL-36γ−/− mice. Additionally, IL-36γ−/− mice develop genital disease more rapidly, have significantly reduced survival time, and exhibit an increased incidence of hind limb paralysis that is linked to productive HSV-2 infection in the brain stem. IL-36γ−/− mice also exhibit a significant delay in clearance of the virus from the vaginal epithelium and a more rapid spread of HSV-2 to the spinal cord, bladder, and colon. We further show that the decreased survival time and increased virus spread observed in IL-36γ−/− mice are not neutrophil-dependent, suggesting that IL-36γ may function to limit HSV-2 spread in the nervous system. Ultimately, we demonstrate that IL-36γ is a key regulator of neutrophil recruitment in the vaginal microenvironment and may function to limit HSV-2 neuroinvasion.

Footnotes

  • This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant 1R15AI113457-01A1 (to M.M.H.-K.).

  • The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the U.S. Centers for Disease Control and Prevention or the Department of Health and Human Services.

  • The online version of this article contains supplemental material.

  • Received March 11, 2019.
  • Accepted September 6, 2019.
  • Copyright © 2019 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (11)
The Journal of Immunology
Vol. 208, Issue 11
1 Jun 2022
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IL-36γ Is a Key Regulator of Neutrophil Infiltration in the Vaginal Microenvironment and Limits Neuroinvasion in Genital HSV-2 Infection
Jameson K. Gardner, Alison Swaims-Kohlmeier, Melissa M. Herbst-Kralovetz
The Journal of Immunology October 2, 2019, ji1900280; DOI: 10.4049/jimmunol.1900280

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IL-36γ Is a Key Regulator of Neutrophil Infiltration in the Vaginal Microenvironment and Limits Neuroinvasion in Genital HSV-2 Infection
Jameson K. Gardner, Alison Swaims-Kohlmeier, Melissa M. Herbst-Kralovetz
The Journal of Immunology October 2, 2019, ji1900280; DOI: 10.4049/jimmunol.1900280
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