Keratinocytes produce IL-17c to protect peripheral nervous systems during human HSV-2 reactivation

• Published in: The Journal of experimental medicine Vol. 214; no. 8; pp. 2315 - 2329
• Main Authors: Peng, Tao, Chanthaphavong, R Savanh, Sun, Sijie, Trigilio, James A, Phasouk, Khamsone, Jin, Lei, Layton, Erik D, Li, Alvason Z, Correnti, Colin E, De van der Schueren, Willem, Vazquez, Julio, O'Day, Diana R, Glass, Ian A, Knipe, David M, Wald, Anna, Corey, Lawrence, Zhu, Jia
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 07.08.2017; The Rockefeller University Press
• Subjects: Activation; Anesthesia; Animals; Apoptosis; Biopsy; Dorsal root ganglia; Fibers; Ganglia; Herpes Genitalis - physiopathology; Herpes Genitalis - virology; Herpes simplex; Herpesvirus 2, Human - physiology; Humans; Infections; Interleukin-17 - physiology; Keratinocytes; Keratinocytes - metabolism; Keratinocytes - virology; Microfluidics; Neurites - physiology; Neuroblastoma - physiopathology; Neurons; Peripheral Nervous System - physiopathology; Peripheral Nervous System - virology; Recurrent infection; Sensory neurons; Skin; Virus Activation - physiology; Viruses
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20160581

Despite frequent herpes simplex virus (HSV) reactivation, peripheral nerve destruction and sensory anesthesia are rare. We discovered that skin biopsies obtained during asymptomatic human HSV-2 reactivation exhibit a higher density of nerve fibers relative to biopsies during virological and clinical quiescence. We evaluated the effects of HSV infection on keratinocytes, the initial target of HSV replication, to better understand this observation. Keratinocytes produced IL-17c during HSV-2 reactivation, and IL-17RE, an IL-17c-specific receptor, was expressed on nerve fibers in human skin and sensory neurons in dorsal root ganglia. In ex vivo experiments, exogenous human IL-17c provided directional guidance and promoted neurite growth and branching in microfluidic devices. Exogenous murine IL-17c pretreatment reduced apoptosis in HSV-2-infected primary neurons. These results suggest that IL-17c is a neurotrophic cytokine that protects peripheral nerve systems during HSV reactivation. This mechanism could explain the lack of nerve damage from recurrent HSV infection and may provide insight to understanding and treating sensory peripheral neuropathies.