Unique Keratinocyte-Specific Effects of Interferon-γ that Protect Skin from Viruses, Identified Using Transcriptional Profiling

Abstract

Interferon (IFN)-γ, is a multifunctional, immunomodulatory cytokine with cell type-specific antiviral activities, particularly important in skin, where it is implicated in many diseases ranging from warts to psoriasis and cancer. Since epidermis is our first line of defence against many viruses, we investigated the molecular processes regulated by IFN-γ in keratinocytes using DNA microarrays. We identified the IFN-γ-regulated keratinocyte-specific genes and antiviral processes. Exclusively in keratinocytes, IFN-γ-induced tight junction proteins, presumably to deny viruses paracellular routes of infection. Furthermore, differing from published data, we find that IFN-γ suppressed the expression of keratinocytes differentiation markers including desmosomal proteins, cornified envelope components and suprabasal cytokeratins. Inhibition of differentiation may interfere with the epidermal tropism of viruses that require differentiating cells for growth, for example, papillomaviruses. As in other cell types, IFN-γ induced HLA, cell adhesion and proteasome proteins, facilitating leukocyte attraction and antigen-presentation by keratinocytes. IFN-γ also induced chemokine/cytokines specific for mononuclear cells. IFN-γ suppressed the expression of over 100 genes responsible for cell cycle, DNA replication and RNA metabolism, thereby shutting down many nuclear processes and denying viruses a healthy cell in which to replicate. Thus, uniquely in keratinocytes, IFN-γ initiates a well-organized molecular programme boosting host antiviral defences, obstructing viral entry, suppressing cell proliferation and impeding differentiation.

Multiple cell types support productive infection and dynamic translocation of infectious Ebola virus to the surface of human skin

“…IFN-γ receptors are present on fibroblasts in the dermis and keratinocytes in the epidermis as well as myeloid populations, consistent with an important role of these cells in skin infection (54,55). We propose that this easily accessible and relevant tissue should be incorporated into antiviral workflows as a highly useful step before animal studies to evaluate drug efficacy.…”

Granulomatous mural folliculitis in 16 domestic goats: Infection with malignant catarrhal fever viruses and colocalization with ovine herpesvirus-2 using in situ hybridization

“…1 Keratinocytes have interferon (IFN)-gamma receptors and when bound by IFN-gamma, either derived from lymphocytes or keratinocytes, outcomes include upregulation of IFN-gamma production (i.e., a positive feedback loop), induction of proteins that prevent or interfere with viral replication, increased antigen presentation via expression of MHC II molecules, and production of chemokines that are specific for monocytes, lymphocytes, and natural killer cells. 1,2,13…”

“…Follicular keratinocytes have a variety of specific functions in physical and immunological defenses, which have led to some authors categorizing them as a type of immune cell. 1 Keratinocytes have interferon (IFN)-gamma receptors and when bound by IFN-gamma, either derived from lymphocytes or keratinocytes, outcomes include upregulation of IFN-gamma production (i.e., a positive feedback loop), induction of proteins that prevent or interfere with viral replication, increased antigen presentation via expression of MHC II molecules, and production of chemokines that are specific for monocytes, lymphocytes, and natural killer cells. 1,2,13 In contrast with the results in this case series, a 2022 case report of caprine GMF with OvHV-2 infection observed OvHV-2 hybridization signal in mononuclear inflammatory cells rather than follicular or epidermal keratinocytes, MNGCs, or endothelial cells.…”

“…1 Keratinocytes have interferon (IFN)-gamma receptors and when bound by IFN-gamma, either derived from lymphocytes or keratinocytes, outcomes include upregulation of IFN-gamma production (i.e., a positive feedback loop), induction of proteins that prevent or interfere with viral replication, increased antigen presentation via expression of MHC II molecules, and production of chemokines that are specific for monocytes, lymphocytes, and natural killer cells. 1,2,13 In contrast with the results in this case series, a 2022 case report of caprine GMF with OvHV-2 infection observed OvHV-2 hybridization signal in mononuclear inflammatory cells rather than follicular or epidermal keratinocytes, MNGCs, or endothelial cells. These infected mononuclear cells were found surrounding lesions of arteritis, transmigrating and surrounding follicles, and within eroded epidermis, possibly suggesting an immune-mediated pathogenesis.…”

Hypertrophic Perianal Herpes Mimicking Squamous Cell Cancer: A Case Report and a Review of the Literature

“…The possible immunological mechanisms for the development of hypertrophic lesions include the production of tumor necrosis factor (TNF)-alpha by an increased number of factor XIII-positive plasmacytoid dendritic cells, promotion of the keratinocyte growth rate and resulting acanthosis and hyperkeratosis. Moreover, decreased IFN-gamma production, which plays an important regulating role in keratinocyte activity, may also help to explain the evolution into the hypertrophic form [7].…”