Topical Application of S1P₂ Antagonist JTE-013 Attenuates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis in Mice

Abstract

Sphingosine-1-phosphate (S1P) and its receptors have been implicated in atopic dermatitis. S1P 2 was found to function as a pro-allergic receptor, while its antagonist JTE-013 was found to suppress allergic asthma in mice. Topical application of JTE-013 has not been investigated in an in vivo model of atopic dermatitis. Therefore, the therapeutic potential of JTE-013 topical application was evaluated by the use of a 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis mouse model. DNCB-induced inflammation and mast cell accumulation in skin tissues were significantly suppressed by topical JTE-013 treatment in BALB/c mice. DNCB-induced increase of lymph nodes sizes and elevated inflammatory cytokines (IL-4, IL-13, IL-17, and IFN-γ) in lymph nodes were also significantly reduced by the JTE-013 treatment. Elevated serum levels of IgE were significantly suppressed by the topical treatment of JTE-013. In summary, the topical treatment of JTE-013 S1P 2 antagonist suppressed DNCB-induced atopic dermatitis symptoms and immune responses. These results suggested JTE-013 as a potential therapeutic agent for atopic dermatitis.

S1P/S1P2 Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide

“…Further, S1P 2 played a pivotal role in the regulation of such events via activating pathways of NF-κB, PI3K, ERK1/2, and ROS. Based on the established roles of the NLRP3 inflammasome and S1P 2 demonstrated in independent studies involving several disease types, such as liver fibrosis [ 37 , 38 ], cerebral ischemia [ 39 , 40 ], and psoriasis [ 41 , 42 ], the current findings suggest a possible clue for the pathogenic mechanism underlying the role of the S1P/S1P 2 signaling axis in tissue injuries. It might also be interesting to pursue the role of this signaling axis in the regulation of macrophage polarization, which is a critical event for immune responses under various tissue injuries since NLRP3 is associated with M1 polarization of macrophages [ 43 , 44 , 45 ].…”

2-Arachidonyl-lysophosphatidylethanolamine Induces Anti-Inflammatory Effects on Macrophages and in Carrageenan-Induced Paw Edema

“…For IL-1β (sense 5′-GGA GAA GCT GTG GCA GCT A-3′, antisense 5′-GCT GAT GTA CCA GTT GGG GA-3′) and IL-6 (sense 5′-TGG GAA ATC GTG GAA ATG AG-3′, antisense 5′-GAA GGA CTC TGG CTT TGT CT-3′), annealing was undertaken at 57 °C. Aliquots (7 µl) were electrophoresed in 1.2% agarose gels and stained with StaySafe TM Nucleic Acid Gel Stain (Real Biotech Corporation, Taipei, Taiwan) [ 10 , 13 ].…”

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 …”

“…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 …”