Keratin 16 regulates innate immunity in response to epidermal barrier breach

Abstract

Mutations in the type I keratin 16 (Krt16) and its partner type II keratin 6 (Krt6a, Krt6b) cause pachyonychia congenita (PC), a disorder typified by dystrophic nails, painful hyperkeratotic calluses in glabrous skin, and lesions involving other epithelial appendages. The pathophysiology of these symptoms and its relationship to settings in which Krt16 and Krt6 are induced in response to epidermal barrier stress are poorly understood. We report that hyperkeratotic calluses arising in the glabrous skin of individuals with PC and Krt16 null mice share a gene expression signature enriched in genes involved in inflammation and innate immunity, in particular damage-associated molecular patterns. Transcriptional hyper-activation of damage-associated molecular pattern genes occurs following de novo chemical or mechanical irritation to ear skin and in spontaneously arising skin lesions in Krt16 null mice. Genome-wide expression analysis of normal mouse tail skin and benign proliferative lesions reveals a tight, context-dependent coregulation of Krt16 and Krt6 with genes involved in skin barrier maintenance and innate immunity. Our results uncover a role for Krt16 in regulating epithelial inflammation that is relevant to genodermatoses, psoriasis, and cancer and suggest a avenue for the therapeutic management of PC and related disorders.

Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes

“…In contrast, we found no remarkable difference in Gsr mRNA ( Figure 1G). Although the mRNA levels of Me2 and G6pd were decreased 5.3 ± 0.2-fold and increased 3.7 ± 0.9-fold, respectively, the overall levels of NADPH were similar fragility (11). A follow-up effort showed that footpad lesions from Krt16 -/-mouse paw skin and biopsies from clinically involved plantar skin in individuals with PC show a remarkably similar molecular signature whereby the expression of genes coding for danger-associated molecular patterns (DAMPs), e.g., alarmins, and regulators of skin barrier formation, is markedly elevated (11).…”

“…Although the mRNA levels of Me2 and G6pd were decreased 5.3 ± 0.2-fold and increased 3.7 ± 0.9-fold, respectively, the overall levels of NADPH were similar fragility (11). A follow-up effort showed that footpad lesions from Krt16 -/-mouse paw skin and biopsies from clinically involved plantar skin in individuals with PC show a remarkably similar molecular signature whereby the expression of genes coding for danger-associated molecular patterns (DAMPs), e.g., alarmins, and regulators of skin barrier formation, is markedly elevated (11). This effort also showed that subjecting clinically uninvolved skin in Krt16 -/-mice to wounding or topically applied chemical irritants results in an exaggerated upregulation of DAMP/alarmin and skin barrier genes relative to controls and, further, that Krt16 is an integral part of a strong genetic network involving such genes (11).…”

“…In part, this likely reflects the fact that K6a, K6b, K16, and K17 have distinct properties and functions among keratins (5). Further, Krt6a, Krt6b, Krt16, and Krt17 are highly inducible upon disruption of homeostasis in most complex epithelia (9,11), and this property likely adds to the chronic and progressively worsening character of PPK lesions in individuals with PC (12). The poor understanding of the pathophysiology of PPK and PC has unfortunately contributed to delays in devising effective treatments in spite of a well-organized patient-and researcher-based effort to combat this disease, as exemplified in the International Pachyonychia Congenita Consortium (IPCC).…”

“…A follow-up effort showed that footpad lesions from Krt16 -/-mouse paw skin and biopsies from clinically involved plantar skin in individuals with PC show a remarkably similar molecular signature whereby the expression of genes coding for danger-associated molecular patterns (DAMPs), e.g., alarmins, and regulators of skin barrier formation, is markedly elevated (11). This effort also showed that subjecting clinically uninvolved skin in Krt16 -/-mice to wounding or topically applied chemical irritants results in an exaggerated upregulation of DAMP/alarmin and skin barrier genes relative to controls and, further, that Krt16 is an integral part of a strong genetic network involving such genes (11). Here, we provide compelling evidence that K16 regulates the function of nuclear factor erythroid-derived 2 related factor 2 (NRF2), a master regulator of cellular responses to oxidative stress and of epidermal homeostasis, suggesting a new avenue for the therapeutic management of PC-associated PPK lesions.…”

Oestrogen promotes healing in a bacterial LPS model of delayed cutaneous wound repair

“…Keratins assemble as pairs, with keratin 16, the type 1 keratin partner of K6, required for the regulation of DAMP expression. 64 Specifically, K16 deficiency leads to cytokine and DAMP overexpression. It is therefore possible that extended expression of these 'wound-type' keratins in LPS-treated wounds may have evolved to suppress a heightened inflammatory response to skin bacteria upon injury.…”