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

Abstract

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.

Novel functions of S1P in chronic itchy and inflammatory skin diseases

“…The effect of S1P in pain and itch responses also requires further elucidation. A lot of evidence is emerging, that S1P pathway modulators ameliorate the severity of skin conditions in animal models, marking them as potential therapeutic agents in humans and implying a reason for further research 49,65,66,71 …”

“…A reduction of epidermal ceramide levels has been observed in a variety of dermatological conditions such as atopic dermatitis, psoriasis and ichthyosis. This might indicate dysregulation of the sphingolipid metabolism which possibly is a contributing factor in disease progression and severity 48–50 . The homeostasis of S1P and its precursors is essential for optimal function and health of the skin, as both increased and decreased levels are associated with disease and dysfunction 51 .…”

“…This might indicate dysregulation of the sphingolipid metabolism which possibly is a contributing factor in disease progression and severity. [48][49][50] The homeostasis of S1P and its precursors is essential for optimal function and health of the skin, as both increased and decreased levels are associated with disease and dysfunction. 51 The expression of the S1P receptors in the skin is not well described, though keratinocytes have been shown to express S1PR 1-5 and Langerhans cells, which are skin-resident macrophages, express S1PR 1, 2 and 4.…”

“…In a mouse model study conducted by Yoon et al In 2020, the S1PR1 and sphingosylphosphorylcholine antagonist KRO-105714 significantly reduced symptoms of AD in the test animals. 49 Moreover, topical as well as systemic application of the specific S1PR2 antagonist JTE-013 has been shown to alleviate symptoms of 2,4-dinitrochlorbenzene-induced AD in mouse models, whilst the inflammatory response of AD was greatly ameliorated in S1PR2 knockout-mice. 64,65…”

Pathogenic sphingosine 1-phosphate pathway in psoriasis: a critical review of its pathogenic significance and potential as a therapeutic target

“…Therefore, the local topical application of S1P can promote early wound healing and later scar repair. Yoon et al [68] reduced angiogenesis in a mouse model of atopic dermatitis using a novel antagonist of S1PR1, which effectively alleviated atopic dermatitis symptoms in vivo/in vitro. Syed et al [24] used imiquimod (IMQ) to induce psoriasis-like dermatitis in a mouse model of myeloid-specific S1PR1 deletion to explore lymphatic versus angiogenesis in conditional knockout mice and found that increased inflammation in mice was associated with increased vascularity but decreased lymphatic vessel density.…”