Cytokines as genetic modifiers in K5^{���/���}mice and in human epidermolysis bullosa simplex

Abstract

Epidermolysis bullosa simplex (EBS) is a skin disorder caused by fully-penetrant mutations in the keratin genes KRT5 and KRT14, leading to extensive cytolysis and cell fragility of basal keratinocytes. EBS is subject to environmental conditions and displays high intra- and interfamilial variability, suggesting modifying loci. Here, we demonstrate that upregulation of certain cytokines accompanies mutations in keratin 5 (K5) but not in keratin 14 (K14). We find for the first time that cytokines macrophage chemotactic protein (MCP)-1/[chemokine (C-C motif) ligand 2] (CCL2), macrophage inflammatory protein (MIP)-3beta/CCL19 and MIP-3alpha/CCL20, all regulated by nuclear factor kappa B (NFkappaB) and involved in the recruitment, maturation, and migration of Langerhans cells (LCs) in the epidermis, are upregulated in the skin of K5(-/-), but not of K14(-/-) mice. In neonatal K5(-/-) epidermis, the number of LCs was increased two-fold. At the same time, tumor necrosis factor alpha (TNFalpha) remained unaltered, demonstrating the specificity of that process. Most remarkably, enhanced LC recruitment within the epidermis was found in five EBS patients carrying mutations in the KRT5 gene but not in EBS patients with KRT14 gene mutations. In agreement with the NFkappaB-dependent regulation of these cytokines, we found a decrease in p120-catenin in the basal epidermis of K5(-/-) mice. These data provide the first explanation for distinct, keratin-type-specific genotype-phenotype correlations in EBS and represent a rationale to investigate gene loci affecting skin pathology in EBS.

Induction of phenotype modifying cytokines by FERMT1 mutations

“…8). FERMT1 mutations lead to upregulation of several cytokines in keratinocytes, similar to cytokine secretion induced by certain keratin mutations in epidermolysis bullosa simplex (Coulombe, et al, 2009;Roth, et al, 2009). In both diseases the mutated proteins, kindlin-1 and keratin 5, are expressed only in epidermal keratinocytes and are associated with maintenance of functional cytoskeletal structures.…”

Keratin intermediate filament proteins – novel regulators of inflammation and immunity in skin

“…This phenotype is remarkably similar to what occurs in epidermolysis bullosa simplex (EBS), a genetic disorder that results from function-abrogating mutations in either KRT5 or its partner KRT14 (Coulombe and Lee, 2012). Prior to birth, the skin of late-stage mouse Krt5-null embryos is mechanically sound in utero, but already shows elevated expression of the pro-inflammatory cytokines Il-6 and Il-1b (Lu et al, 2007) and Ccl2 and Ccl20, correlating with an increased density of antigen-presenting Langerhans dendritic cells in their epidermis (Roth et al, 2009). Coincidentally, individuals that suffer from EBS as a result of mutations at the KRT5 locus show an increased density of Langerhans cells in the epidermis, a phenomenon that is not seen in EBS cases that are associated with KRT14 mutations or in Krt14-null mice (Roth et al, 2009).…”

“…Prior to birth, the skin of late-stage mouse Krt5-null embryos is mechanically sound in utero, but already shows elevated expression of the pro-inflammatory cytokines Il-6 and Il-1b (Lu et al, 2007) and Ccl2 and Ccl20, correlating with an increased density of antigen-presenting Langerhans dendritic cells in their epidermis (Roth et al, 2009). Coincidentally, individuals that suffer from EBS as a result of mutations at the KRT5 locus show an increased density of Langerhans cells in the epidermis, a phenomenon that is not seen in EBS cases that are associated with KRT14 mutations or in Krt14-null mice (Roth et al, 2009). Finally, the genetic loss of Krt17 results in a delay in the inception of basaloid tumors in Gli2 transgenic mouse skin, which correlates with reduced tumor keratinocyte proliferation and a global cytokine switch, from what should be a Th1-and/or Th17-dominated to a Th2-dominated immune profile, in skin tumors (DePianto et al, 2010) (Fig.…”

Keratins provide virus-dependent protection or predisposition to injury in coxsackievirus-induced pancreatitis

“…42 Another apparent difference is the response of K19 topographical distribution in CVB4-indued versus caeruleininduced pancreatitis. In the CVB4-induced pancreatitis, K19 was not found in WT C-filaments of recovering acini ( Figure 6) as reported in the caerulein model where K19 forms temporarily extended CFs during the regenerationphase.…”