Inter‐α‐trypsin inhibitor heavy chain 5 (ITIH5) is overexpressed in inflammatory skin diseases and affects epidermal morphology in constitutive knockout mice and murine 3D skin models

Abstract

Inter-α-trypsin inhibitors are protease inhibitors that are thought to be important regulators in various acute-phase processes. They are composed of one light chain (bikunin) and different heavy chains (ITIHs). The only function known so far of ITIHs is the covalent linkage to hyaluronan (HA). As there is virtually no knowledge on the distribution and function of ITIH proteins in skin tissue, we performed a systematic characterization of ITIH expression in healthy and diseased skin. Using GeneChip(®) Human Exon 1.0 ST expression profiling, we found that ITIH5 represents the major ITIH family member expressed in human skin. Moreover, the use of quantitative reverse transcription PCR and a customized ITIH5-specific antibody indicated that ITIH5 is predominantly produced by dermal fibroblasts. Immunohistochemical analysis revealed a clearly detectable ITIH5 protein expression in normal skin. Interestingly, ITIH5 expression was significantly up-regulated in inflammatory skin diseases. Furthermore, 3D skin models employing murine Itih5(-/-) epidermal keratinocytes and dermal fibroblasts as well as skin specimens of Itih5(-/-) mice revealed a significantly altered epidermal structure compared to wild-type controls. Hence, we can strengthen the presumption that ITIH5 may constitute a novel regulatory molecule of the human skin that could play an important role in inflammation via its interaction with HA.

Chronic sun exposure is associated with distinct histone acetylation changes in human skin

“…Moreover, during many inflammatory events, the ITIH–hyaluronan complex significantly promotes the adhesion of leucocytes . Recent studies have revealed that ITIH5 expression is significantly upregulated in inflammatory skin diseases . In this study, we found that the PDCD5 and ITIH5 promoter regions were significantly hyperacetylated at histone H3 in sun‐exposed skin.…”

Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor β1 (TGFβ1)-dependent Fibroblast to Myofibroblast Differentiation

“…A recent study also found that HC5 was the major heavy chain expressed in skin, predominantly due to its production by dermal fibroblasts (43). The authors conclude that HC5 may play an important role in inflammation through its interaction with HA.…”

“…Blots shown are representative of four experiments. Top, Western blot showing that the amount of I␣I heavy chain 5 present was markedly increased following stimulation with TGF␤1 Bottom, following TGF␤1 incubation, the cells were treated with 10 g/ml trypsin in PBS for 10 min at room temperature as shown previously to remove any cell surface/CD44-associated HA (43). C, cells were incubated with or without TGF␤1 (10 ng/ml) for 72 h. The cells were then either left untreated or exposed to Streptomyces hyaluronidase (0.4 units in 400 l of PBS for 2 h).…”

Ontogeny of inter‐alpha inhibitor protein (IAIP) expression in human brain

“…Although many of the mechanisms underlying the functional importance of IAIPs are not known, increases in IAIP expression are correlated with a diverse spectrum of pathological conditions including tissue injury and repair (Huth et al, 2015;Plaas et al, 2011;Tan, McGrouther, Day, Milner, & Bayat, 2011), and inflammation (Daveau et al, 1998;Garantziotis et al, 2007;Itoh et al, 1994;Kobayashi, 2006;Mizon, Mairie, Balduyck, Hachulla, & Mizon, 2001;Okroj et al, 2012;Seifert, Kurzinger, Hopt, & Wittel, 2013;Wakahara et al, 2005). Recent studies have also reported changes in the level of IAIPs after stroke (Kashyap et al, 2009) and Alzheimer's disease (Shi et al, 2019), suggesting that endogenous IAIPs may be integrally related to the pathogenesis of inflammatory-related brain disorders.…”