Sexual Dimorphism in Response to an NRF2 Inducer in a Model for Pachyonychia Congenita

Abstract

Sex is an influential factor regarding pathophysiology and therapeutic response in human disease. Pachyonychia congenita (PC) is caused by mutations in keratin genes and typified by dystrophic lesions affecting nails, glands, oral mucosa, and palmar-plantar epidermis. Painful palmar-plantar keratoderma (PPK) severely impair mobility in PC. Mice genetically null for keratin 16 (Krt16), one of the genes mutated in PC, develop PC-like PPK. In male Krt16-/- mice, oxidative stress associated with impaired glutathione synthesis and NRF2-dependent gene expression precedes PPK onset, which can be prevented by topical sulforaphane (SF)-mediated activation of NRF2 (Kerns et al., J. Clin. Invest. 126:2356-66). We report here that SF treatment fails to activate NRF2 and prevent PPK in female Krt16-/- mice despite a similar set of molecular circumstances. Follow-up studies reveal a temporal shift in PPK onset in Krt16-/- females, coinciding with sex-specific fluctuations in footpad skin glutathione levels. Dual treatment with SF and diarylproprionitrile (DPN), an estrogen receptor beta (ER-β) selective agonist, results in NRF2 activation, normalization of glutathione levels, and prevention of PPK in female Krt16-/- mice. These findings point to a sex difference in NRF2 responsiveness that needs be considered when exploring NRF2 as a therapeutic target in skin disorders.

A role for keratins in supporting mitochondrial organization and function in skin keratinocytes

“…Secondly, we do not know whether the mitochondrial dysfunction is leading to increased ROS production or if the damage is a result of an already established oxidative stress. This is significant because activation of oxidative stress pathways precedes PPK lesions in mice and reducing oxidative stress in PC patients ameliorates symptoms [12,42]. These finding reported herein provide a platform to answer these questions and provide a truer picture of keratins active role in regulating mitochondrial function, structure and dynamics.…”

“…Keratin proteins play a multifaceted role in keratinocyte homeostasis, and mutations in keratin genes lead to a diverse range of phenotypic outcomes. The K6/K16 keratin pairing, which is robustly wound-inducible, supports and promotes a number of cellular functions including structural integrity [17,24,39], cell migration [8,40], keratinocyte differentiation [41], regulation of innate immunity [7] and redox homeostasis [12,42]. Disruption of many of these cellular functions is poised to play a role in the pathophysiology of PC, in particular, in oral and palmoplantar keratoderma lesions [43].…”

Sex Matters: Interfering with the Oxidative Stress Response in Pachyonychia Congenita

“…Figure 1. Images of typical PC symptoms and schematic representation of main results described by Kerns et al (2018). (a, b) The images of (a) plantar hyperkeratosis and (b) nail thickening of two PC patients were kindly provided by the Pachyonychia Congenita Project (www.pachyonychia.org).…”

“…Building on these findings, Kerns et al (2018) hypothesized that stimulating estrogen receptor-b, which is known to positively affect NRF2 signaling and, conversely, inhibiting estrogen receptora activity, which has been shown to activate NRF2 signaling, might overcome the SF resistance of female mice. This hypothesis was tested using diarylpropionitrile (DPN), which is an estrogen receptor-b selective agonist and estrogen receptor-a antagonist.…”

“…We report and comment on an article by Kerns et al (2018) PC is a very rare skin disease that presents exorbitant nail thickening and painful palmoplantar keratoderma (PPK) (Figure 1a and b). It has been linked to dominant negative mutations in the genes encoding the type II keratins K6a and K6b and their keratin type I polymerization partners K16 and K17 (http://www.interfil.org).…”