Extracellular signaling molecules mediate the communication between cells or tissues. These can be small proteins (peptides), large proteins, lipids, protein and lipid complexes, carbohydrates, gases, amino acids, nucleic acids, amino acids, and various small organic molecules. These signals can function locally, affecting cells that are near the cells producing the signal, or can function systemically as hormones, traveling in the circulation to affect distant tissues and cells. Paracrine signals are those that affect nearby cells, autocrine signals are those that affect the cell producing the signal. Many signaling molecules are multifunctional and belong to multiple categories. For example, many paracrine signals are also autocrine signals and some local signals can also be released into the circulation to function as endocrine signals with systemic actions.
Many signaling molecules are multifunctional and belong to multiple categories.
Some signaling molecules are named for the source or the cells between which they signal. Neurotransmitters mediate signals between neurons and from neurons, adipokines are signals from fat cells, and myokines are signals from muscle cells. The signals released by bone cells are called osteokines, although that term is not widely used. All of these represent cytokines, that is signals produced by cells. However, the term cytokine is often used in a more restricted way to mean the protein signals used to mediate immune responses, such as for communicating with the cells in the immune system and between the cells of the immune system.
Growth factors were so named because they make tissues grow, primarily by stimulating the division of cells. However, most growth factors have multiple functions. They can not only stimulate cell division, but they can also stimulate cell movement or differentiation or they can enhance cell survival. Growth factors can be subcategorized by the type of cells that they target. For example, neurotrophic factors are growth factors for nerves. Like many growth factors, neurotrophic factors not only can stimulate nerve cells to divide, but they can promote survival, stimulate differentiation, and change the morphology (shape) of the cells, in this case by stimulating the formation of processes called neurites.
This multifunctionality can wreak havoc with the human classification schemes for defining signaling molecules. The highlighted article describes an example of a “rule-breaking” signal, in this case a cytokine released by skin cells that functions as a neurotrophic factor for sensory nerves.
Peng and colleagues (1) studied herpes simplex virus 2 (HSV-2) (Figure 1), which is a virus that causes genital herpes. HSV-2 infects the skin but lies dormant as a latent virus in the sensory nerves until it is reactivated. Despite using the nerves for the HSV latent state and to carry the viral particles back to the skin to reactivate the infection, repeated HSV reactivation does not cause loss of feeling or persistent pain at the site of reactivation. This is different from another latent herpes virus infection, varicella zoster, which when reactivated often does cause persistent pain (called postherpetic neuropathy).
The authors discovered that the skin at the place where the virus was reactivated produced a cytokine, interleukin-17c (IL-17c) and that this cytokine exerted three effects on nerves. IL-17c enhanced survival of infected nerves, stimulated the nerves to form processes called neurites, and guided the neurites where to grow. IL-17c had been previously identified as a cytokine released by epithelial cells in the skin and intestine that acted as an autocrine signal for the epithelial cells and altered the ability of the epithelial cells to respond to inflammation (2). Thus, IL-17c functions as a typical cytokine. It is a signal that regulates what is called the “innate” immune response, which enables every cell, not just immune cells, to respond to infection and injury.
The authors (1) analyzed human biopsy samples from skin with an HSV-2 lesion, an asymptomatic virally active area, a healed area, and a noninfected area. Compared with areas of noninfected skin, peripheral nerves were denser in the asymptomatic active areas and the nerve fibers were longer in the healed area. To identify molecules that were produced by keratinocytes, a type of skin cell, that could cause these changes in the peripheral nerves, the authors used a technique called laser capture microdissection to isolate keratinocytes from the different skin regions. Then they analyzed the changes in gene expression in the keratinocytes from areas of HSV-2 lesions or healed areas. Among the genes that had increased expression in these areas were 3 that were classified as encoding cytokines: IL-17c, CCL5, and TNFSF10. Indeed, antibody staining for IL-17c in the skin samples showed that IL-17c was present in small groups of keratinocytes in only the skin from lesions or healed lesions. The receptor for IL-17c was detected on the neuronal processes in the skin from areas with a lesion, healed areas, and noninfected areas.
Moving to cells in culture, the authors (1) determined that both keratinocytes and nerves produced IL-17c when infected with HSV-2. Adding a pure form of IL-17c to human sensory neurons in culture stimulated the growth of longer neurites that grew faster than those on nerves grown in the presence of a known neurotrophic factor, conveniently called nerve growth factor (NGF). The neurites also grew toward a source of IL-17c, consistent with this cytokine serving as a directional guidance cue for the nerves. Using mouse neurons in culture, the authors showed that IL-17c reduced cell death in response to HSV-2 infection.
The cell culture experiments did not include any immune cells. Therefore, these studies with the cultured cells showed that IL-17c mediates a signal from the keratinocytes to the nerves and did not require cells of the immune system to promote neuron survival and neurite growth. Instead, these data indicate that skin experiencing HSV-2 infection releases IL-17c, which maintains neuronal survival and promotes the growth of neurites into the infected area. This study does not examine how the IL-17c and other cytokines produced by the skin affect the immune response to the viral infection. However, this study defines a neurotrophic activity for a cytokine, which defies easy categorization. IL-17c is an epithelial autocrine signal that functions as a cytokine mediating innate immune responses and an epithelial-produced paracrine signal that functions as a neurotrophic factor.
This study defines a neurotrophic activity for a cytokine, which defies easy categorization.
- T. Peng, S. Chanthapghavong, S. Sun, J. A. Trigilio, K. K. Phasouk, L. Jin, E. D. Layton, A. Z. Li, C. E. Correnti, W. De van der Schueren, J. Vazquez, D. R. O’Day, I. A. Glass, D. M. Knipe, A. Wald, L. Corey, J. Zhu, Keratinocytes produce IL-17c to protect peripheral nervous systems during human HSV-2 reactivation. J. Exp. Med. (June 2017) DOI: 10.1084/jem.20160581. PubMed
- V. Ramirez-Carrozzi, A. Sambandam, E. Luis, Z. Lin, S. Jeet, J. Lesch, J. Hackney, J. Kim, M. Zhou, J. Lai, Z. Modrusan. T. Sai, W. Lee, M. Xu, P. Caplazi, L. Diehl. J. de Voss, M. Malazs, L. Bonzalez, Jr., H. Sing, W. Ouynag, R. Pappu, IL-17C regulates the innate immune function of epithelial cells in an autocrine manner. Nat. Immunol. 12, 1159–1166 (2011). PubMed
Cite as: N. R. Gough, HSV-Infected Skin Signals to Nerves. BioSerendipity (24 July 2017) https://www.bioserendipity.com/2017/07/24/hsv-infected-skin-signals-to-nerves/.