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Inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is a natural stabilizer of hyaluronan that modulates biological processes in the skin

ABSTRACT: Hyaluronan (HA) is a major component of the skin that exerts a variety of biological functions. Inter-α-trypsin inhibitor heavy chain (ITIH) proteins comprise a family of hyaladherins of which ITIH5 was recently described in skin, playing a functional role in skin morphology and inflammatory skin diseases including allergic contact dermatitis (ACD). The current study focused on the ITIH5-HA interaction and its potential clinical and functional impact in extracellular matrix (ECM) stabilization. Using murine skin models, ITIH5 knockdown fibroblasts and a reactive oxygen species (ROS)-mediated HA degradation assay we proved that ITIH5 binds to HA thereby acting as a stabilizer of HA. Moreover, micro-array profiling revealed the impact of ITIH5 on biological processes such as skin development and ECM homeostasis. To understand more precisely the role of ITIH5 in inflammatory skin diseases such as ACD we generated ITIH5 knockout cells of the KeratinoSens cell line. Performing the in vitro KeratinoSens skin sensitization assay, we detected that ITIH5 decreases the sensitizing potential of moderate and strong contact sensitizers. Taken together, our experiments revealed that ITIH5 forms complexes with HA, thereby on the one hand stabilizing HA and facilitating the formation of ECM structures and on the other hand modulating inflammatory responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE141495 | GEO | 2019/12/05

REPOSITORIES: GEO

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Project description:Genes involved in the inflammatory response resulting in allergic contact dermatitis (ACD) are only partly known. In this study, we introduce the use of high density oligonucleotide arrays for gene expression profiling in human skin during the elicitation of ACD. Skin biopsies from normal and nickel-exposed skin were obtained from 7 nickel-allergic patients and 5 non-allergic controls at four different time points during elicitation of eczema: 0h, 7h, 48h and 96h. Each gene expression profile was analysed by hybridization to high density oligonucletide arrays. Cluster analysis of 74 genes found to be differentially expressed in the patients over time revealed that the patient samples may be categorised into two groups: An early time point group (0h and 7h) and a late time point group (48h and 96h). Compared to the early time points, late time point skin samples were characterised by the up-regulation of inflammatory molecules including genes involved in the class I antigen presenting pathway and genes involved in lymphocyte adhesion and motility ; Correspondence analysis including both patients and controls revealed three distinct groups: i) the control group, ii) the early time point patient group (0h and 7h) and iii) the late time point patient group (48h and 96h). Experiment Overall Design: For the microarray study, 7 nickel-allergic patients and 5 non-allergic controls were recruited. All subjects were female. The skin covering the upper nates was exposed to nickel delivered during a patch test. Skin biopsies were taken to generate a time-series. Skin was exposed to nickel for 0h, 7h, 48h and 96h. Experiment Overall Design: All nickel allergic patients reacted with visible eczama at the 48h and 96h time-points. No eczema was vissible at the 0h or 7h time-points. Control subjects did not show visible eczema at any time-point. Experiment Overall Design: RNA was extracted from the skin biopsies and 34 biopsies yielded RNA of sufficient quantity and quality for micro-array analysis.

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Inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is a natural stabilizer of hyaluronan that modulates biological processes in the skin

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