Unbalanced Sphingolipid Metabolism and Its Implications for the Pathogenesis of Psoriasis

Abstract

Sphingolipids (SLs), which have structural and biological responsibilities in the human epidermis, are importantly involved in the maintenance of the skin barrier and regulate cellular processes, such as the proliferation, differentiation and apoptosis of keratinocytes (KCs). As many dermatologic diseases, including psoriasis (PsO), intricately characterized by perturbations in these cellular processes, are associated with altered composition and unbalanced metabolism of epidermal SLs, more education to precisely determine the role of SLs, especially in the pathogenesis of skin disorders, is needed. PsO is caused by a complex interplay between skin barrier disruption, immune dysregulation, host genetics and environmental triggers. The contribution of particular cellular compartments and organelles in SL metabolism, a process related to dysfunction of lysosomes in PsO, seems to have a significant impact on lysosomal signalling linked to a modulation of the immune-mediated inflammation accompanying this dermatosis and is not fully understood. It is also worth noting that a prominent skin disorder, such as PsO, has diminished levels of the main epidermal SL ceramide (Cer), reflecting altered SL metabolism, that may contribute not only to pathogenesis but also to disease severity and/or progression. This review provides a brief synopsis of the implications of SLs in PsO, aims to elucidate the roles of these molecules in complex cellular processes deregulated in diseased skin tissue and highlights the need for increased research in the field. The significance of SLs as structural and signalling molecules and their actions in inflammation, in which these components are factors responsible for vascular endothelium abnormalities in the development of PsO, are discussed.

Keywords: lysosomal dysfunction; pathogenesis of psoriasis; skin barrier disruption; sphingolipid metabolism alterations.

Figure 1

Key pathways of sphingolipid metabolism. De novo synthesis (1) of ceramide occurs mainly on the outer membrane. Ketosphinganine is formed as a result of the condensation of palmityl-CoA and serine. In the next stage, 3-ketosphinganine is rapidly converted to sphinganine. A fatty acid residue is attached to the sphinganine molecule, resulting in the formation of dihydroceramide. The final stage of de novo ceramide synthesis is desaturation, consisting in the formation of a double bond between carbons 4 and 5 in a dihydroceramide molecule. Then, ceramide is transported to the Golgi apparatus and metabolised to other sphingolipid groups. In lysosomes, the synthesis of ceramide from sphingosine under the influence of ceramide synthase is called the salvage pathway (2), where complex sphingolipids are digested to sphingosine, which can be transported to various cellular compartments. Ceramide may also be synthesized in the mitochondria-associated membranes (3).

Figure 2

Role of the ceramide (Cer) and sphingosine-1-phosphate (S1P) in keratinocyte apoptosis and survival. Ceramide (activated by FasL or TNF-α) acts as a secondary lipid transmitter leads to apoptosis through stimulation of specific protein targets, such as P38-MAPK, PKCζ or JNK and inhibition of Akt kinase activity or through direct permeabilization of the mitochondrial membrane and release of cytochrome c into the cytoplasm. S1P acts as a ceramide antagonist, promoting cell survival by blocking a BIM-dependent signalling cascade, thus preventing the release of cytochrome c from mitochondria or by activating Akt. Akt—protein kinase B; BAK—Bcl-2 homologous antagonist killer; BAX—apoptosis regulator BAX; Bcl-xL—B-cell lymphoma-extra-large; BIM—Bcl-2-like protein 11; FasL—fas ligand; JNK—c-Jun N-terminal kinase; MCL-1—induced myeloid leukaemia cell differentiation protein; P38-MAPK—p38 mitogen-activated protein kinase; PKCζ—protein kinase C zeta type; ROS—reactive oxygen species; S1P—sphingosine-1-phosphate; S1PR—sphingosine-1-phosphate receptor; TNF-α—tumour necrosis factor alpha and TNFR—tumour necrosis factor receptor.

Figure 3

Role of ceramide (Cer) and sphingosine-1-phosphate (S1P) in the functions of vascular endothelium. S1P is necessary for maintenance of proper vascular integrity and promotion of angiogenesis. It is also a molecule that activate the migration of endothelial cells and protect adherent junctions. Cer is involved in programmed endothelial cell death, senescence and cell cycle arrest, leading to increased vascular permeability endothelial barrier dysfunction.