Abstract
Interface dermatitis is a histopathological pattern mirroring a distinct cytotoxic immune response shared by a number of clinically diverse inflammatory skin diseases amongst which lichen planus and cutaneous lupus erythematosus are considered prototypic. Interface dermatitis is characterized by pronounced cytotoxic immune cell infiltration and necroptotic keratinocytes at the dermoepidermal junction. The initial inflammatory reaction is established by cytotoxic immune cells that express CXC chemokine receptor 3 and lesional keratinocytes that produce corresponding ligands, CXC motif ligands 9/10/11, recruiting the effector cells to the site of inflammation. During the resulting anti-epithelial attack, endogenous immune complexes and nucleic acids are released from perishing keratinocytes, which are then perceived by the innate immune system as danger signals. Keratinocytes express a distinct signature of pattern recognition receptors and binding of endogenous nucleic acid motifs to these receptors results in interferon-mediated immune responses and further enhancement of CXC chemokine receptor 3 ligand production. In this perspective article, we will discuss the role of innate nucleic acid sensing as a common mechanism in the perpetuation of clinically heterogeneous diseases featuring interface dermatitis based on own data and a review of the literature. Furthermore, we will introduce a keratinocyte-specific in vitro model of interface dermatitis as follows: Stimulation of human keratinocytes with endogenous nucleic acids alone and in combination with interferon gamma leads to pronounced production of distinct cytokines, which are essential in the pathogenesis of interface dermatitis. This experimental approach bears the capability to investigate potential therapeutics in this group of diseases with unmet medical need.
Highlights
Interface dermatitis (ID), referred to as lichenoid tissue reaction, describes a histopathological pattern defined by morphological anomalies of the epidermal basal cell layer characterized by perishing keratinocytes labeled vacuolar or hydropic colloid bodies
CXCL10 and MxA are Expressed by Keratinocytes in Interface Dermatitis and the Majority of Infiltrating Immune Cells Express CXCR3 Receptors Figure 1A depicts findings within a lichen planus (LP) skin specimen that are representative for all examined samples: MxA (MX Dynamin Like GTPase A) and CXCL10 are expressed by keratinocytes and the majority of infiltrating immune cells carries CXCR3 receptors
Stimulation With Interferon gamma (IFNy) and Endogenous Nucleic Acids Induce CXCL10 and MxA Expression Stimulation with IFNy or endogenous nucleic acids (eNA) respectively leads to significant expression of CXCL10 in HaCaT cells
Summary
Interface dermatitis (ID), referred to as lichenoid tissue reaction, describes a histopathological pattern defined by morphological anomalies of the epidermal basal cell layer characterized by perishing keratinocytes labeled vacuolar or hydropic colloid bodies. In 1995, for the first time, Fäh et al detected MxA expression in virally infected tissue and in dermatoses featuring ID [4]. These findings are explained by MxA expression being directly induced by type-I and type-III IFNs [5]. Stimulation with eNA results in a pronounced expression of typical ID-associated cytokines within different keratinocyte models. IFNy, mainly produced by lymphocytes, is known to play a pivotal role in the pathogenesis of diseases featuring ID [107,108,109], and has been shown to induce typical morphological changes in human epidermis equivalents, in vitro [110]. The ability to reduce MTT reagent into its insoluble formazan was significantly impaired in both HaCaT (Figure 2B) and HEK (Figure 2C) serving as a marker for cell viability
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