12R-lipoxygenase deficiency disrupts epidermal barrier function.
12R-lipoxygenase (12R-LOX) and the epidermal LOX-3 (eLOX-3) constitute a novel LOX pathway involved in terminal differentiation in skin. This view is supported by recent studies showing that inactivating mutations in 12R-LOX and eLOX-3 are linked to the development of autosomal recessive congenital ichthyosis. We show that 12R-LOX deficiency in mice results in a severe impairment of skin barrier function. Loss of barrier function occurs without alterations in proliferation and stratified organization of the keratinocytes, but is associated with ultrastructural anomalies in the upper granular layer, suggesting perturbance of the assembly/extrusion of lamellar bodies. Cornified envelopes from skin of 12R-LOX-deficient mice show increased fragility. Lipid analysis demonstrates a disordered composition of ceramides, in particular a decrease of ester-bound ceramide species. Moreover, processing of profilaggrin to monomeric filaggrin is impaired. This study indicates that the 12R-LOX-eLOX-3 pathway plays a key role in the process of epidermal barrier acquisition by affecting lipid metabolism, as well as protein processing.
Epp
Nikolas
N
Section Eicosanoids and Tumor Development, German Cancer Research Center, D-69120 Heidelberg, Germany.
Fürstenberger
Gerhard
G
Müller
Karsten
K
de Juanes
Silvia
S
Leitges
Michael
M
Hausser
Ingrid
I
Thieme
Florian
F
Liebisch
Gerhard
G
Schmitz
Gerd
G
Krieg
Peter
P
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase; D002463:Cell Membrane Permeability; D049109:Cell Proliferation; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology*; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D050356:Lipid Metabolism; D008084:Lipoxygenase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D008084:Lipoxygenase; C518403:eLOX3 protein, mouse; C520168:Alox12b protein, mouse; D001092:Arachidonate 12-Lipoxygenase