|Year : 2022 | Volume
| Issue : 1 | Page : 14-19
Prenatal infection predisposes offspring to enhanced susceptibility to imiquimod-mediated psoriasiform dermatitis in mice
Sebastian Yu1, Chia-Wen Lee2, Yu-An Li2, Tsung-Hsi Chen3, Hsin-Su Yu4
1 Department of Dermatology, College of Medicine; Department of Dermatology, Kaohsiung Medical University Hospital; Graduate Institute of Clinical Medicine, College of Medicine; Neuroscience Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
2 Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
3 School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
4 Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
|Date of Submission||21-Sep-2021|
|Date of Decision||01-Jan-2022|
|Date of Acceptance||08-Feb-2022|
|Date of Web Publication||30-Mar-2022|
Dr. Hsin-Su Yu
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung
Source of Support: None, Conflict of Interest: None
Background: Infection can upregulate T helper 17 (Th17) signaling and exacerbate psoriasis. Literature has indicated that prenatal infection induces embryonic development toward Th17 signaling and is a risk factor for developing certain Th17-skewing disorders such as autism in offspring. However, it remains unclear if a prenatal infection is a risk factor for developing psoriasis in offspring. Objectives: We investigated if a prenatal infection predisposes mice offspring to enhanced susceptibility to psoriatic inflammation. Methods: Pregnant C57BL/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid poly I:C to simulate prenatal bacterial and viral infection, respectively. Phosphate-buffered saline (PBS) injection was used as the control. When mice offspring were at the age of 9–10 weeks, imiquimod (IMQ) cream or control vehicle was applied topically on ears for 5 consecutive days to induce psoriasiform dermatitis. The extent of epidermal hyperplasia and the number of Munro microabscesses were examined by histologic analysis. Protein expressions of neutrophil marker Ly6 g and Th17-associated cytokines were measured by western blotting. Results: Prenatal infection with LPS or poly I:C induced a greater extent of epidermal hyperplasia and more Munro microabscesses after IMQ application as compared with prenatal PBS injection. Mice offspring with prenatal infection also had higher protein expressions of Ly6 g, IL-17a, and interleukin-23 after IMQ stimulation compared with their PBS controls. Conclusion: Prenatal infection predisposes mice offspring to enhanced susceptibility to IMQ-mediated psoriasiform dermatitis. The data obtained from the present animal study suggest that prenatal infection might be a risk factor for developing psoriasis in offspring.
Keywords: Bacterial infection, lipopolysaccharide, polyinosinic:polycytidylic acid, psoriasis, psoriatic arthritis, viral infection
|How to cite this article:|
Yu S, Lee CW, Li YA, Chen TH, Yu HS. Prenatal infection predisposes offspring to enhanced susceptibility to imiquimod-mediated psoriasiform dermatitis in mice. Dermatol Sin 2022;40:14-9
|How to cite this URL:|
Yu S, Lee CW, Li YA, Chen TH, Yu HS. Prenatal infection predisposes offspring to enhanced susceptibility to imiquimod-mediated psoriasiform dermatitis in mice. Dermatol Sin [serial online] 2022 [cited 2022 Dec 3];40:14-9. Available from: https://www.dermsinica.org/text.asp?2022/40/1/14/341356
| Introduction|| |
Psoriasis is a chronic inflammatory disease with typical cutaneous lesions and multiple comorbidities, including arthritis.,,,, T helper 17 (Th17) signaling plays a pivotal role in the immune mechanisms of psoriasis. In recent years, biologic agents such as blocking upstream interleukin-23 (IL-23) and downstream IL-17 cytokines of Th17 signaling have made tremendous progress in therapeutics of psoriasis, further supporting the importance of Th17 signaling in the pathogenesis of psoriasis.
The prevalence of psoriasis varies in different countries and ethnic groups. The prevalence of psoriasis in western countries varies from 0.91% to 8.5%, while the prevalence is lower in Asian countries, ranging from 0.24% to 0.47%.,, The difference in prevalence may result from the distinct genetic background and environmental factors. Recent literature has indicated that Western diets enhance Th17 signaling and predispose psoriasiform inflammation in murine models.,, It is worth investigating if other environmental factors upregulating Th17 signaling could predispose psoriasis.
Certain bacterial, viral, and fungal infections polarize the immune system toward Th17 signaling.,, Prenatal infection is a known risk factor for developing Th-17 mediated disorders such as autism and schizophrenia., Specifically, prenatal infection alters the developmental programming of the immune system and induces preferential differentiation toward Th17 cells. While the infection is an exacerbating factor for preexisting psoriasis, it is unclear if prenatal infection predisposes offspring to develop psoriasis. Intriguingly, an epidemiologic study shows that prenatal exposure to stressful events may contribute to the development of psoriasis. In views of prenatal stress may predispose offspring to develop psoriasis, we hypothesize that prenatal infection is a risk factor for developing psoriasis in offspring. In the present study, we show that prenatal infection with lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid poly I:C, which simulate bacterial and viral infection, respectively, could predispose offspring to enhanced susceptibility to imiquimod (IMQ)-induced psoriasiform dermatitis in mice.
| Materials and Methods|| |
Mice and prenatal infection models
The pregnant wild-type C57BL/6 mice were purchased from Lasco (Yilan, Taiwan). LPS (LPS, Escherichia More Details coli 055: B5)
(L2880, Merck, Darmstadt, Germany) was injected intraperitoneally into pregnant wild-type C57BL/6 mice at 120 μg/kg, at day 15 of gestation. Phosphate-buffered saline (PBS) injection was used as a control. To further examine if different infectious sources would lead to different results, the viral mimic poly I:C (P9582, Merck, Darmstadt, Germany) at 5 mg/kg at day 15 of gestation instead of LPS was intraperitoneally injected as an alternative prenatal infection model. Offspring mice were weaned at postnatal day 28. Offspring mice were randomly assigned into group rearing (three mice per cage). Offspring mice exposed to prenatal infection were defined as the experimental group, while offspring from pregnant mice which received PBS injection were controls. Animal protocols were approved by the Institutional Animal Care and Use Committee of Kaohsiung Medical University (IACUC number 106043).
Imiquimod-induced psoriasis model
When offspring mice were at the age of 9-10 weeks, mice were treated on each ear with 10 mg 5% IMQ cream (Aldara, 3M Company, Maplewood, Minnesota, USA) or control vehicle cream (Vaseline, Unilever, London, UK) for 5 consecutive days, and ear thickness was measured daily using a Peacock G-1A dial thickness gauge (Ozaki MFG, Tokyo, Japan).,,,,,,
Formaldehyde-fixed, paraffin-embedded ear skin samples were stained with hematoxylin and eosin H&E stain. We used TissueFAXS Histo (TissueGnostics GmbH, Vienna, Austria) to collect images and used computer-assisted quantitative image analysis software (ImageJ) to measure epidermal length and thickness. The number of Munro microabscesses was calculated by two people independently.
We extracted proteins from the harvested ear tissues using T-PERTM Tissue Protein Extraction Reagent (78510, ThermoFisher, Waltham, Massachusetts, USA) with proteinase inhibitor (4906845001, Roche, Basel, Switzerland) and phosphatase inhibitor (4693159001, Roche). Protein concentrations were determined using protein assay dye (5000006, Bio-Rad, Hercules, California, USA). Total protein (15 μg) was loaded into a 15% polyacrylamide gel and run at 60V for 4 h. After electrophoresis, the protein was transferred to a polyvinylidene difluoride membrane at 400 mA for 90 min and blocked for HyBlock 1 min Blocking Buffer in TBST (W-3401, Goal Bio, Taipei, Taiwan). The membrane was then incubated with the primary antibodies against Actin (1:2000; MAB1501, Merck, Darmstadt, Germany), IL17a (1:1500; 26163-1-AP, Proteintech, Chicago, Illinois, USA), IL22 (1:1000; AF582, R&D Systems, Minneapolis, Minnesota, USA), IL23a (1:500; 14-7232-81, ThermoFisher), and Ly6G (1:500; 14-5931-82, ThermoFisher) at 4°C overnight. After five washes in wash buffer (1X TBST), the membrane was incubated with corresponding secondary antibodies, horseradish peroxidase (HRP)-conjugated anti-mouse (1:5000; AP124P, Merck, Darmstadt, Germany), HRP-conjugated anti-rabbit (1:5000; 111-035-144, Jackson Immuno Research, West Grove, Pennsylvania, USA), HRP-conjugated anti-goat (1:5000; 3150052, Merck, Darmstadt, Germany), and HRP-conjugated anti-rat (1:5000; SA00001-15, Proteintech, Chicago, Illinois, USA) at room temperature for 1 h and chemiluminescence was detected using Western Lightning® ECL Pro (NEL122001EA, PerkinElmer, Waltham, Massachusetts, USA). Films were developed using Cold Light Imaging Analysis (MiniChemi, SageCreation, Beijing, China). Computer-assisted quantitative image analysis software (ImageJ) was used for quantitative analysis of detected bands.
All data were analyzed using GraphPad Prism 8.0. The results were described using mean ± standard deviation. Two-way analysis of variance was used to analyze the differences in Munro microabscesses, epidermal thickness, and protein expressions among groups. P < 0.05 was considered statistically significant.
| Results|| |
Prenatal infection with lipopolysaccharide or poly I:C enhanced imiquimod-induced epidermal hyperplasia in mice offspring
We applied topical IMQ on both ears of mice offspring for 5 consecutive days and measured ear thickness as a marker of skin inflammation. Mice offspring of LPS, poly I:C, and PBS groups had significantly more ear swelling during the 5-day IMQ protocol as compared with their control vehicle counterparts [Figure 1]a, [Figure 1]b, [Figure 1]c. The extent of ear swelling was not significantly different among LPS, poly I:C, and PBS groups [Figure 1]d. Since the ear includes not only the epidermis but also dermis, muscle, and cartilage, we specifically measured epidermal thickness to examine if the extent of epidermal hyperplasia induced by IMQ differs among the three groups. By histological analysis, the epidermis of LPS and poly I:C groups was thicker than that of PBS controls after the 5-day IMQ protocol [Figure 1]e and [Figure 1]f.
|Figure 1: Prenatal infection with lipopolysaccharide or polyinosinic:polycytidylic acid enhances imiquimod-induced epidermal hyperplasia in mice offspring. imiquimod and Vaseline was applied to both ears of mice offspring for 5 consecutive days, and ear thickness was measured daily. (a-c) showed ear thickness change of lipopolysaccharide, polyinosinic:polycytidylic acid, and phosphate-buffered saline groups, respectively. Imiquimod-induced prominent ear swelling as compared with Vaseline in all three groups. (d) showed that there was no significant difference in imiquimod-induced ear swelling among the three groups. The thickness of the epidermis was measured under microscopic view, and (e) showed that both lipopolysaccharide and polyinosinic:polycytidylic acid groups had thicker epidermis than phosphate-buffered saline controls after the 5-day imiquimod application. Representative photos were shown in (f). LPS: Lipopolysaccharide. Poly I:C: Polyinosinic:polycytidylic acid, PBS: Phosphate-buffered saline, IMQ: Imiquimod, *: P < 0.05, **: P < 0.01, ***: P < 0.001, ****: P < 0.0001.|
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Mice offspring with prenatal infection with lipopolysaccharide or poly I:C have more neutrophils and Munro microabscess after imiquimod stimulation than phosphate-buffered saline control mice
Next, we asked if the epidermal hyperplasia is associated with psoriasiform characteristics. Of note, mice offspring of LPS and poly I:C groups have higher densities of Munro microabscesses, a pathognomonic feature of psoriasis, than their PBS counterparts [Figure 2]a. In consistent with that finding, western blotting showed higher protein expression of neutrophil marker Ly6 g [Figure 2]b [Supplementary Figure 1]. These results indicated that prenatal infection with LPS or poly I:C enhanced susceptibility to IMQ-induced psoriasiform dermatitis in mice offspring.
|Figure 2: Mice offspring with lipopolysaccharide or polyinosinic:polycytidylic acid prenatal infection develop more Munro microabscesses after 5-day imiquimod application. (a) Showed the density of Munro microabscesses, which was calculated as the number of Munro microabscess divided by the length of epidermis (millimeter). Protein expression level of Ly6G was examined by western blotting. (b) Showed that both lipopolysaccharide and polyinosinic:polycytidylic acid groups had more Ly6G expression than phosphate-buffered saline controls. LPS: Lipopolysaccharide, Poly I:C: Polyinosinic:polycytidylic acid, PBS: Phosphate-buffered saline, IMQ: Imiquimod. *: P < 0.05, **: P < 0.01, ****: P < 0.0001, ns: Not significant.|
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Mice offspring with prenatal infection with lipopolysaccharide or poly I:C have higher protein expressions of psoriasis-related cytokines after imiquimod stimulation compared with their phosphate-buffered saline control counterparts
We next asked if Th17-associated cytokines are responsible for the different extent of IMQ-induced psoriasiform dermatitis between mice offspring with prenatal infection and PBS control mice. Protein expression levels of IL-17a, which is crucial for neutrophil recruitment and psoriatic inflammation, were significantly higher in IMQ-treated ears of LPS and poly I:C mice offspring than IMQ-treated ears of PBS controls [Figure 3]a [Supplementary Figure 1]. Protein expression level of IL-23a, another protein that plays a central role in psoriatic inflammation, were also significantly higher in IMQ-treated ears of LPS and poly I:C mice offspring as compared with IMQ-treated ears of PBS controls [Figure 3]b [Supplementary Figure 1]. Next, we examined if protein expression of IL-22 differs between experimental groups and controls. Intriguingly, poly I:C mice offspring had higher IL-22 expression than both LPS mice offspring and PBS controls, while there was no difference between LPS and PBS groups [Figure 3]c [Supplementary Figure 1]. Taken together, these results indicated that prenatal infection with either LPS or poly I:C predisposes mice offspring to enhanced Th17 signaling upon IMQ stimulation.
|Figure 3: Prenatal infection with lipopolysaccharide or polyinosinic:polycytidylic acid induces higher expression of T helper 17-associated cytokines. (a) Showed that protein expression of IL-17a was significantly higher in lipopolysaccharide and polyinosinic:polycytidylic acid groups after 5-day imiquimod protocol. (b) Showed both lipopolysaccharide and polyinosinic:polycytidylic acid groups had higher expression of IL-23a. (c) showed, protein expression of IL-22 was significantly higher in polyinosinic:polycytidylic acid group, while the expression was not different between lipopolysaccharide and phosphate-buffered saline groups. (d) showed the sample size in each group. LPS: Lipopolysaccharide. Poly I:C: Polyinosinic:polycytidylic acid, PBS: Phosphate-buffered saline, IMQ: Imiquimod, *: P < 0.05, **: P < 0.01, ****: P < 0.0001, ns: Not significant.|
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| Discussion|| |
The present study shows that prenatal infection enhances IMQ-induced psoriasiform dermatitis in the skin of mice offspring. After IMQ 5-day stimulation, both mice with maternal prenatal infection of LPS and mice with maternal prenatal infection of poly I:C have higher protein expression levels of IL-23a and IL-17a in the skin compared with mice with maternal prenatal PBS injection. The mechanisms underlying the upregulation of Th17 signaling remain to be elucidated, but previous autism studies using murine models have indicated that viral infection induces maternal immune activation (MIA) and IL-17a is required for MIA-induced abnormalities in mice offspring.,
It is noteworthy that IL-22 expression differs between LPS and poly I:C groups in the present study. Although IL-22 contributes to epidermal hyperplasia and is regarded as a key cytokine in the pathogenesis of psoriasis, there is still no therapeutics blocking IL-22 clinically approved for psoriasis. In view that mice offspring of prenatal infection with LPS do not have increased expression of IL-22 but still have enhanced psoriasiform dermatitis upon IMQ stimulation, it might be possible that IL-23 and IL-17a are more important than IL-22 in terms of initiating the development of psoriasis, at least in infection-related predisposition.
Considering prenatal infection is a well-known risk factor for schizophrenia, a Th17-skewing neuropsychiatric disease,,,, it could be hypothesized that prenatal infection might simultaneously predispose offspring to psoriatic inflammation and schizophrenia-like behavior. Indeed, our previous research and recent literature have indicated that patients with schizophrenia have a higher risk of developing psoriasis, although the mechanisms underlying the association remain elusive.,, The prenatal infection models established in the present study may provide a research platform for investigating the mechanisms and possible brain-skin communications.
| Conclusion|| |
This is the first study to demonstrate that prenatal infection could enhance susceptibility to psoriasiform dermatitis in mice. Skewing of Th17 cytokines including IL-17 and IL-23 may be responsible for the enhanced susceptibility. Further epidemiologic studies are warranted to investigate if a prenatal infection is a risk factor for developing psoriasis in human offspring.
Financial support and sponsorship
This study was supported by grants from the Taiwan Ministry of Science and Technology (MOST-108-2314-B-037-081, MOST-108-2628-B-037-004, MOST-109-2628-B-037-013, and MOST-110-2628-B-037-007) to SY and grants from Kaohsiung Medical University Hospital (KMUH108-8T03, KMUH108-8R57, and KMUH109-9R67, KMUH110-0R61) to SY. This study is supported partially by Kaohsiung Medical University Research Center Grant (KMU-TC109B03 and KMU-TC110B03).
Conflicts of interest
Prof. Hsin-Su Yu, an editorial board member at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.
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[Figure 1], [Figure 2], [Figure 3]