(R)-Salbutamol Improves Imiquimod-Induced Psoriasis-Like Skin Dermatitis by Regulating the Th17/Tregs Balance and Glycerophospholipid Metabolism
<p>Experimental procedure of the antipsoriatic activity evaluation of (<span class="html-italic">R</span>)-salbutamol or Dex. one hour after the administration of different doses of (<span class="html-italic">R</span>)-salbutamol or Dex twice per day, mice in all groups except for the control group received a daily topical dose of 62.50 mg of the imiquimod (IMQ) cream on the shaved area of their backs for seven consecutive days. On day 8, the mice were killed to harvest specimens for experiments.</p> "> Figure 2
<p>(<span class="html-italic">R</span>)-salbutamol alleviates psoriatic dermatitis. Phenotypical presentation of mouse back skin from control, IMQ, (<span class="html-italic">R</span>)-salbutamol and Dex groups after seven days of treatment, respectively (<b>A</b>). Distinct levels of erythema (<b>B</b>), skin thickeness (<b>C</b>), scaling (<b>D</b>) of back skin was scored daily on a scale from 0 to 4. Additionally, the cumulative score (<b>E</b>) (erythema plus scaling plus thickness) is depicted. <span class="html-italic">n</span> = 8, Mean ± SD, <sup>†</sup> <span class="html-italic">p</span> < 0.05, <sup>††</sup> <span class="html-italic">p</span> < 0.01 vs. IMQ group, ** <span class="html-italic">p</span> < 0.01 vs. control group.</p> "> Figure 3
<p>Treatment with (<span class="html-italic">R</span>)-salbutamol ameliorated the morphological changes induced by IMQ. (<b>A</b>) (<span class="html-italic">R</span>)-salbutamol improves pathological injury. (Scale bar: 200 µm) White arrows show inflammatory cell infiltration, gray arrows show parakeratosis, red arrows represent Munro’s microabscesses, and black arrows was thickened prickle cell layer of the epidermis. (<b>B</b>) (<span class="html-italic">R</span>)-salbutamol alleviates epidermal thickness of the dorsal skin on day 8. (<b>C</b>) (<span class="html-italic">R</span>)-salbutamol decreased Baker score. <sup>#</sup> <span class="html-italic">p</span> < 0.05, <sup>##</sup> <span class="html-italic">p</span> < 0.01, compared with IMQ group. ** <span class="html-italic">p</span> < 0.01, compared with control group. Each bar represents the mean ± SD (<span class="html-italic">n</span> = 8).</p> "> Figure 4
<p>(<span class="html-italic">R</span>)-salbutamol reduced the levels of leukocytes in the blood and reduced IL-17 in the plasma. (<b>A</b>) white blood cells (WBC), (<b>B</b>) Neutrophil, (<b>C</b>) Monocyte were analyzed using IDEXX ProCyte DX hematology analyzer. (<b>D</b>) Levels of IL-17 in mouse plasma were measured by ELISA. <sup>#</sup> <span class="html-italic">p</span> < 0.05, <sup>##</sup> <span class="html-italic">p</span> < 0.01, compared with IMQ group. ** <span class="html-italic">p</span> < 0.01, compared with control group. Each bar represents the mean ± SD (<span class="html-italic">n</span> = 8).</p> "> Figure 5
<p>Effect of (<span class="html-italic">R</span>)-salbutamol treatment on the ratio of spleen weight to bodyweight. (<b>A</b>) Representative photographs of spleen in different groups. (<b>B</b>) 24 h after the final administration, mice were sacrificed and the ratio of spleen weight to bodyweight was determined. <sup>###</sup> <span class="html-italic">p</span> < 0.01, compared with IMQ group. *** <span class="html-italic">p</span> < 0.001, compared with control group. Each bar represents the mean ± SD (<span class="html-italic">n</span> = 8).</p> "> Figure 6
<p>The influence of (<span class="html-italic">R</span>)-salbutamol on Th17 cells and Treg cells levels. Spleen cells were obtained from mice on day 8 and then stimulated with cocktail (with Brefeldin) for 6 h. Thereafter, they were stained with fluorescent conjugated anti-mouse CD3, CD25, and CD4. In addition, intracellular staining of IL-17 and Foxp3 was performed using the respective antibodies. Representative contour plots showed the frequency of live CD4+ T cells, IL-17+ Th17 gated and CD25+ Foxp3+ Treg in the splenocytes isolated from mice treated with IMQ and then with (<span class="html-italic">R</span>)-salbutamol. Relative scatter plots showed the frequencies determined from live cells. (<b>A</b>) Representative dot plots showing the percentage of CD3+CD4+ T cells. (<b>B</b>) Statistical analysis of the percentage of CD3+CD4+ T cells. (<b>C</b>) Expression of intracellular cytokines IL-17 was detected by flow cytometry in cells gated for CD4+. (<b>D</b>) FoxP3 stained with a Foxp3 staining buffer set without stimulation, with CD25+ surface as the gate. (<b>E</b>,<b>F</b>) Statistical analysis of the above results. <sup>##</sup> <span class="html-italic">p</span> < 0.01, relative to IMQ group. ** <span class="html-italic">p</span> < 0.01, relative to the control group. Error bars represent the mean ± SD (<span class="html-italic">n</span> = 8).</p> "> Figure 7
<p>Results of the metabolic effects of (<span class="html-italic">R</span>)-salbutamol in mice treated with IMQ to induce psoriasis. (<b>A</b>,<b>B</b>) PCA plot scores for the control, IMQ and (<span class="html-italic">R</span>)-salbutamol (L, M, H) groups in (<b>B</b>) ESI (−) mode and (A) ESI (+). (<b>C</b>,<b>D</b>) PLS-DA score plot for the (<span class="html-italic">R</span>)-salbutamol (L, M, H), IMQ and control on the basis of mice plasma metabolic profiles for the (<b>D</b>) ESI (−) mode and (C) ESI (+). (<b>E</b>,<b>F</b>) Venn diagrams showing the upregulated (<b>E</b>) or downregulated metabolites (<b>F</b>) based on the binary comparison of (<span class="html-italic">R</span>)-salbutamol vs. control, IMQ vs. control corresponding to the numbers shown in <a href="#app1-cells-09-00511" class="html-app">Supplemental Table S4</a>. (<b>G</b>,<b>H</b>) Volcano plots of <span class="html-italic">p</span> values in the (<b>G</b>) ESI (+) and (H) ESI (−) mode. (<b>I</b>) Visualization of candidate biomarkers among the (<span class="html-italic">R</span>)-salbutamol, IMQ, and control in the ESI (+) and ESI (−) mode using Heat map of unsupervised hierarchical clustering. Columns: samples; Rows: biomarkers. The content level of metabolites is denoted by the color key. Red stands for high metabolite level whereas blue color denotes low metabolite level. (<b>J</b>) Pathway analysis for the differential metabolism in the (<span class="html-italic">R</span>)-salbutamol (L, M, H), IMQ, and control groups based on the topology analysis (<span class="html-italic">x</span>-axis) and enrichment analysis scores (<span class="html-italic">y</span>-axis). The size and color of each circle represent the pathway impact factor and <span class="html-italic">p</span>-value, respectively. The pathways marked in red are the most significant. These analyses were performed using the MetaboAnalyst 4.0 tool.</p> "> Figure 8
<p>Abundant of some metabolites in plasma of mice from control, IMQ and (<span class="html-italic">R</span>)-salbutamol groups. <sup>#</sup> <span class="html-italic">p</span> < 0.05, <sup>##</sup> <span class="html-italic">p</span> < 0.01, relative to IMQ group. ** <span class="html-italic">p</span> < 0.01, relative to the control group.</p> "> Figure 9
<p>Schematic diagram showing possible mechanisms responsible for the pharmacological efficacy of (<span class="html-italic">R</span>)-salbutamol. Oral administration of (<span class="html-italic">R</span>)-salbutamol markedly reduced the plasma levels of IL-17, decreased the proportion of CD4+ Th17+ T cells (Th17) whereas increased the percentage of CD25+ Foxp3+ regulatory T cells (Tregs) in the spleens, and affected glycerophospholipid metabolism.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Mice Treatments
2.3. Evaluating the Severity of Skin Inflammation
2.4. Histopathological Examination
2.5. Hematological Analysis
2.6. IL-17 ELISA
2.7. Intracellular Staining and Flow Cytometry
2.8. Metabolomic Analysis
2.9. Statistical Analysis
3. Results
3.1. (R)-Salbutamol Alleviates Psoriatic Dermatiti
3.2. (R)-Salbutamol Alleviates the Pathology Changes Alterations Caused by IMQ on Mice Skin
3.3. Effect of (R)-Salbutamol on Haematological Parameters of IMQ-Induced Mouse Psoriasis
3.4. (R)-Salbutamol Reduced IL-17 Secretion in Mice Plasma
3.5. Effect of (R)-Salbutamol Treatment on the Ratio of Spleen Weight to Body Weight
3.6. (R)-Salbutamol Immune-Regulates the Number of CD3+CD4+ T Cells in Mice Treated with IMQ
3.7. The Influence of (R)-Salbutamol on Metabolic Effects of IMQ Treatment
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Liu, F.; Wang, S.; Liu, B.; Wang, Y.; Tan, W. (R)-Salbutamol Improves Imiquimod-Induced Psoriasis-Like Skin Dermatitis by Regulating the Th17/Tregs Balance and Glycerophospholipid Metabolism. Cells 2020, 9, 511. https://doi.org/10.3390/cells9020511
Liu F, Wang S, Liu B, Wang Y, Tan W. (R)-Salbutamol Improves Imiquimod-Induced Psoriasis-Like Skin Dermatitis by Regulating the Th17/Tregs Balance and Glycerophospholipid Metabolism. Cells. 2020; 9(2):511. https://doi.org/10.3390/cells9020511
Chicago/Turabian StyleLiu, Fei, Shanping Wang, Bo Liu, Yukun Wang, and Wen Tan. 2020. "(R)-Salbutamol Improves Imiquimod-Induced Psoriasis-Like Skin Dermatitis by Regulating the Th17/Tregs Balance and Glycerophospholipid Metabolism" Cells 9, no. 2: 511. https://doi.org/10.3390/cells9020511