Sphingolipids and Inflammatory Diseases of the Skin

Kleuser, Burkhard; Japtok, Lukasz

doi:10.1007/978-3-7091-1511-4_18

Cited by 14 publications

(9 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With the exception of TFEB, the MiT family of transcription factors include MITF, involved in melanogenesis; TFE3, which promotes the expression of genes downstream of transforming growth factor beta (TGFβ) signaling; and TFEC, which plays a role in cell survival, growth, and differentiation. With respect to lysosomal metabolism studies in this field, an interesting observation is the dysregulation of sphingolipid metabolism, in particular alterations in ceramides being a central hub of the sphingolipid pathway, in inflammatory skin diseases such as psoriasis and atopic dermatitis [39]. Sphingolipids, as bioactive molecules with a putative involvement in inflammation, play an important role in epidermal signaling [40].…”

Section: Discussionmentioning

confidence: 99%

Lysosome Alterations in the Human Epithelial Cell Line HaCaT and Skin Specimens: Relevance to Psoriasis

Bocheńska

Moskot

Malinowska

et al. 2019

IJMS

View full text Add to dashboard Cite

Despite the constantly updated knowledge regarding the alterations occurring in the cells of patients with psoriasis, the status and the role of the lysosome, a control center of cell metabolism, remain to be elucidated. The architecture of the epidermis is largely regulated by the action of lysosomes, possibly activating signaling pathways in the cellular crosstalk of keratinocytes—epidermal cells—with infiltrating immune cells. Thus, in the present study, lysosome alterations were examined in vitro and in situ using a two-dimensional (2D) keratinocyte model of HaCaT cells with “psoriasis-like” inflammation and skin specimens, respectively. Specific fluorescence and immunohistochemical staining showed an augmented level of acidic organelles in response to keratinocyte activation (mimicking a psoriatic condition while maintaining the membrane integrity of these structures) as compared with the control, similar to that seen in skin samples taken from patients. Interestingly, patients with the most pronounced PASI (Psoriasis Area and Severity Index), BSA (Body Surface Area), and DLQI (Dermatology Life Quality Index) scores suffered a high incidence of positive lysosomal-associated membrane protein 1 (LAMP1) expression. Moreover, it was found that the gene deregulation pattern was comparable in lesioned (PP) and non-lesioned (PN) patient-derived skin tissue, which may indicate that these alterations occur prior to the onset of the characteristic phenotype of the disease. Changes in the activity of genes encoding the microphthalmia family (MiT family) of transcription factors and mammalian target of rapamycin complex 1 (MTORC1) were also observed in the in vitro psoriasis model, indicating that the biogenesis pathway of this arm is inhibited. Interestingly, in contrast to the keratinocytes of HaCaT with “psoriasis-like” inflammation, LAMP1 was up-regulated in both PP and PN skin, which can be a potential sign of an alternative mechanism of lysosome formation. Defining the molecular profile of psoriasis in the context of “the awesome lysosome” is not only interesting, but also desired; therefore, it is believed that this paper will serve to encourage other researchers to conduct further studies on this subject.

show abstract

Section: Discussionmentioning

confidence: 99%

Lysosome Alterations in the Human Epithelial Cell Line HaCaT and Skin Specimens: Relevance to Psoriasis

Bocheńska

Moskot

Malinowska

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…SPC and S1P/S1P1 are known as important players in the pathological pathways of atopic dermatitis. In previous reports [6][7][8], the concentration of SPC is increased in atopic dermatitis lesions of clinical patients and a concomitant decrease in ceramide levels is regarded as a pathogenic factor, because Sphingomyelin (SM) is metabolized to ceramide by sphingomyelinase (SMase) or alternatively metabolized SPC by SM deacylase [33,34]. SPC functions as a signal transducer in various cellular processes, such as proliferation, differentiation, migration and apoptosis, and works as an important mediator of atopic dermatitis [2,10].…”

Section: Discussionmentioning

confidence: 99%

“…SPC functions as a signal transducer in various cellular processes, such as proliferation, differentiation, migration and apoptosis, and works as an important mediator of atopic dermatitis [2,10]. Moreover, SPC is known as a stimulation factor for multiple immune cells, such as monocytes and macrophages, to amplify inflammation in many inflammatory diseases [34]. Thus, the level of SPC in skin inflammatory lesions might be an indicator of atopic dermatitis.…”

Section: Discussionmentioning

confidence: 99%

A novel sphingosylphosphorylcholine and sphingosine-1-phosphate receptor 1 antagonist, KRO-105714, for alleviating atopic dermatitis

et al. 2020

View full text Add to dashboard Cite

Background: Atopic dermatitis (eczema) is a type of inflammation of the skin, which presents with itchy, red, swollen, and cracked skin. The high global incidence of atopic dermatitis makes it one of the major skin diseases threatening public health. Sphingosylphosphorylcholine (SPC) and sphingosine-1-phosphate (S1P) act as proinflammatory mediators, as an angiogenesis factor and a mitogen in skin fibroblasts, respectively, both of which are important biological responses to atopic dermatitis. The SPC level is known to be elevated in atopic dermatitis, resulting from abnormal expression of sphingomyelin (SM) deacylase, accompanied by a deficiency in ceramide. Also, S1P and its receptor, sphingosine-1-phosphate receptor 1 (S1P1) are important targets in treating atopic dermatitis. Results: In this study, we found a novel antagonist of SPC and S1P1, KRO-105714, by screening 10,000 compounds. To screen the compounds, we used an SPC-induced cell proliferation assay based on a high-throughput screening (HTS) system and a human S1P1 protein-based [ 35 S]-GTPγS binding assay. In addition, we confirmed the inhibitory effects of KRO-105714 on atopic dermatitis through related cell-based assays, including a tube formation assay, a cell migration assay, and an ELISA assay on inflammatory cytokines. Finally, we confirmed that KRO-105714 alleviates atopic dermatitis symptoms in a series of mouse models. Conclusions: Taken together, our data suggest that SPC and S1P1 antagonist KRO-105714 has the potential to alleviate atopic dermatitis.

show abstract

“…In the case of AD patients, a de novo enzyme was identified, named sphingomyelin/glucosylceramide deacetylase, which catalyzes the hydrolysis of glucosylceramide or sphingomyelin at the level of the acyl group. In these patients, it has an activity increased five-fold when compared to normal individuals [19]. This massive increase explains the reduced levels of both CR and sphingosine.…”

Section: Pathophysiologymentioning

confidence: 99%

Trends in Atopic Dermatitis—From Standard Pharmacotherapy to Novel Drug Delivery Systems

Souto

Dias-Ferreira

Oliveira

et al. 2019

IJMS

View full text Add to dashboard Cite

Atopic dermatitis (AD) is a predominant and deteriorating chronic inflammation of the skin, categorized by robust burning and eczematous lacerations in diverse portions of the body. AD affects about 20% of both offspring and adults worldwide. The pathophysiology of AD combines environmental, hereditary, and immunological aspects, together with skin barrier dysfunction. The procedures used to prevent the disease are the everyday usage of creams to support the restoration of the epidermal barrier. The classical treatments include the use of topical corticosteroids as a first-line therapy, but also calcineurin inhibitors, antihistamines, antibiotics, phototherapy, and also immunosuppressant drugs in severe cases of AD. Topical drug delivery to deeper skin layers is a difficult task due to the skin anatomic barrier, which limits deeper penetration of drugs. Groundbreaking drug delivery systems, based on nanoparticles (NPs), have received much attention due to their ability to improve solubility, bioavailability, diffusion, targeting to specific types of cells, and limiting the secondary effects of the drugs employed in the treatment of AD. Even so, additional studies are still required to recognize the toxicological characteristics and long-term safety of NPs. This review discusses the current classical pharmacotherapy of AD against new nanoparticle skin delivery systems and their toxicologic risks. a prevalence of atopic conditions, as allergic rhinitis or bronchial asthma, and food allergies [2]. Topical administration of drugs is still the main therapeutic approach for AD. Despite this, several disadvantages may be cited as reduced patient compliance (a consequence of adverse effects as skin irritation or allergy), low efficiency, and specificity of these systems in delivering therapeutic drugs [3]. Innovative drug delivery systems should, therefore, exhibit the capacity to penetrate the stratum corneum (SC), which is naturally impermeable to a range of substances, in order to reduce adverse effects and increase drug targeting [3][4][5]. There is still no medication capable of reversing the pathological effects of AD. However, formulations based on nanoparticles (NPs) have been exploited for topical administration of drugs and are expected to overcome the above-mentioned limitations [6][7][8]. PathophysiologyAD, also called atopic eczema, is the most common skin disease, characterized by a pattern of pruritus, skin deterioration, and chronic inflammation [1,6,7]. This illness affects individuals in early-, mid-or late-stages of their lives and does not have a known cure so far. Over the course of the disease, the levels of IgE increase drastically leading to cutaneous signals that appear in early ages and persist until late stages of life, when they begin to disappear. Because of this, AD is also labelled as "allergic march" [2].AD results from a multiplicity of factors such as environmental injuries, impairments against the natural barrier of the skin and response of the immune system. This latter enhances the ac...

show abstract

Sphingolipids and Inflammatory Diseases of the Skin

Cited by 14 publications

References 78 publications

Lysosome Alterations in the Human Epithelial Cell Line HaCaT and Skin Specimens: Relevance to Psoriasis

Lysosome Alterations in the Human Epithelial Cell Line HaCaT and Skin Specimens: Relevance to Psoriasis

A novel sphingosylphosphorylcholine and sphingosine-1-phosphate receptor 1 antagonist, KRO-105714, for alleviating atopic dermatitis

Trends in Atopic Dermatitis—From Standard Pharmacotherapy to Novel Drug Delivery Systems

Contact Info

Product

Resources

About