Suprabasin-null mice retain skin barrier function and show high contact hypersensitivity to nickel upon oral nickel loading

Abstract

Suprabasin (SBSn) is expressed not only in epidermis but also in epithelial cells of the upper digestive tract where metals such as nickel are absorbed. We have recently shown that SBSn level is decreased in the stratum corneum and serum of atopic dermatitis (AD) patients, especially in intrinsic AD, which is characterized by metal allergy. By using SBSn-null (Sbsn-/-) mice, this study was conducted to investigate the outcome of SBSN deficiency in relation to AD. Sbsn-/mice exhibited skin barrier dysfunction on embryonic day 16.5, but after birth, their barrier function was not perturbed despite the presence of ultrastructural changes in stratum corneum and keratohyalin granules. Sbsn-/mice showed a comparable ovalbumin-specific skin immune response to wild type (WT) mice and rather lower contact hypersensitivity (cHS) responses to haptens than did Wt mice. the blood nickel level after oral feeding of nickel was significantly higher in Sbsn-/mice than in Wt mice, and cHS to nickel was elevated in Sbsn-/mice under nickel-loading condition. our study suggests that the completely SBSN deficient mice retain normal barrier function, but harbor abnormal upper digestive tract epithelium that promotes nickel absorption and high cHS to nickel, sharing the features of intrinsic AD.

Suprabasin—A Review

“…The role of SBSN in immune regulation is strengthened with recent observation in Sbsn -null mice [ 36 ]. This animal model showed no aberration in skin development.…”

“…This animal model showed no aberration in skin development. However, following the low-dose nickel challenge, the mice did not develop T regulatory cells (Tregs) in the spleen, suggesting that SBSN is crucial in Treg development induced with these stimuli [ 36 ]. Other possibilities, such as induction of Treg development in general or induction of anergy in the tumour microenvironment specifically need to be evaluated in future studies.…”

“…As already mentioned, the physiological function of SBSN is currently unknown. Sbsn knockout mice do not manifest any abnormal skin phenotype [ 36 ], but shRNA-mediated SBSN knockdown abrogated the development of stratum granulosum , disrupted the formation of keratohyalin granules, and affected the morphology of some keratinocytes in the human living skin equivalent model [ 37 ]. The secretory nature of SBSN isoforms is supported by a number of reports [ 2 , 7 , 32 , 38 , 39 , 40 ], and the SBSN treatment promoted phenotypic changes in vitro [ 12 ], indicating the existence of SBSN receptor(s).…”

Intrinsic Atopic Dermatitis and Extrinsic Atopic Dermatitis: Similarities and Differences

“…And the SBSN −/− mice exhibit intact skin barrier function, but abnormal upper digestive tract epithelium that presents increased Ni absorption and high allergy to Ni, which is similar in intrinsic AD. 50 The implication of Sbsn's deficiency in human intrinsic AD warrants further investigation.…”

New Family Members of FG Repeat Proteins and Their Unexplored Roles During Phase Separation

“…In an RHE model, deficiency in suprabasin caused immature keratohyalin granules but did not affect the other markers of epidermal differentiation. Suprabasin-null mice showed skin barrier dysfunction as embryos but not after birth, and ultrastructural abnormalities in the stratum corneum and immature keratohyalin granules were observed ( Nakazawa et al, 2020 ). Furthermore, the amount of suprabasin was significantly decreased in atopic dermatitis patients ( Sakabe et al, 2014 ; Li et al, 2018 ).…”