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

J Immunol. 2019 Nov 15;203(10):2655-2664. doi: 10.4049/jimmunol.1900280. Epub 2019 Oct 2.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Epithelium / immunology
  • Epithelium / virology
  • Female
  • Gene Knockout Techniques
  • Herpes Genitalis / immunology*
  • Herpes Genitalis / virology
  • Herpesvirus 2, Human / immunology*
  • Immunity, Innate
  • Interleukin-1 / genetics
  • Interleukin-1 / pharmacology*
  • Leukocyte Count
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuroprotective Agents / pharmacology*
  • Neutrophil Infiltration / drug effects*
  • Neutrophil Infiltration / immunology
  • Neutrophils / metabolism
  • Vagina / immunology*
  • Vagina / virology

Substances

  • IL1F9 protein, mouse
  • Interleukin-1
  • Neuroprotective Agents