Loricrin and NRF2 Coordinate Cornification

Yosuke Ishitsuka; Tatsuya Ogawa; Yoshiyuki Nakamura; Noriko Kubota; Yasuhiro Fujisawa; Rei Watanabe; Naoko Okiyama; Manabu Fujimoto; Dennis R Roop; Akemi Ishida-Yamamoto

doi:10.1016/j.xjidi.2021.100065

Loricrin and NRF2 Coordinate Cornification

JID Innov. 2021 Oct 15;2(1):100065. doi: 10.1016/j.xjidi.2021.100065. eCollection 2022 Jan.

Affiliations

¹ Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan.
² Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
³ Department of Dermatology and Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
⁴ Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.

Abstract

Cornification involves cytoskeletal cross-linkages in corneocytes (the brick) and the secretion of lipids/adhesion structures to the interstitial space (the mortar). Because the assembly of lipid envelopes precedes corneocyte maturation, loricrin is supposed to be dispensable for the protection against desiccation. Although the phenotypes of Lor knockout (LKO) mice are obscure, the antioxidative response on the KEAP1/NRF2 signaling pathway compensates for the structural defect in utero. In this study, we asked how the compensatory response is evoked after the defects are repaired. To this end, the postnatal phenotypes of LKO mice were analyzed with particular attention to the permeability barrier function primarily maintained by the mortar. Ultrastructural analysis revealed substantially thinner cornified cell envelopes and increased numbers of lamellar granules in LKO mice. Superficial epidermal damages triggered the adaptive repairing responses that evoke the NRF2-dependent upregulation of genes associated with lamellar granule secretion in LKO mice. We also found that corneodesmosomes are less degraded in LKO mice. The observation suggests that loricrin and NRF2 are important effectors of cornification, in which proteins need to be secreted, cross-linked, and degraded in a coordinated manner.

Keywords: CD, corneodesmosome; CDSN, corneodesmosin; CE, cornified envelope; CEf, immature/fragile cornified envelope; DKO, Lor–Nrf2 double knockout; DMF, dimethyl fumarate; K, keratin; KC, keratinocyte; LG, lamellar granule; LKO, Lor knockout; LOR, loricrin; NKO, Nrf2 knockout; SC, stratum corneum; SG, stratum granulosum; TEWL, transepidermal water loss; TS, tape-stripping; WT, wild type.