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

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.

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