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Dysregulated microRNA expression in IL-4 transgenic mice, an animal model of atopic dermatitis

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Abstract

IL-4 plays an important role in the pathogenesis of atopic dermatitis (AD). Previously we showed that the expression of genes in chemotaxis, angiogenesis, inflammation and barrier functions is dysregulated in IL-4 transgenic (Tg) mice, a well-characterized AD mouse model. In this study, we aim to study differential expression of microRNAs in IL-4 Tg mice. As compared with wild-type mice, we found that 10 and 79 microRNAs are dysregulated in the skin of IL-4 mice before and after the onset of skin lesions, respectively. Bioinformatic analysis and previous reports show that these dysregulated microRNAs may be involved in the NF-κB, TLRs, IL-4/IL-13, MAPK and other pathways. We also found that miR-139-5p and miR-196b-3p are significantly up-regulated in the peripheral blood of IL-4 Tg mice. Taken together, our data have identified many dysregulated microRNAs in IL-4 Tg mice, which may play important roles in AD pathogenesis and pathophysiology.

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Abbreviations

AD:

Atopic dermatitis

FDR:

False discovery rate

GO:

Gene Ontology

IPA:

Ingenuity pathway analysis

Tg:

Transgenic

References

  1. Aggarwal BB, Shishodia S, Takada Y, Jackson-Bernitsas D, Ahn KS, Sethi G, Ichikawa H (2005) TNF blockade: an inflammatory issue. In: Numerof R, Dinarello CA, Asadullah K (eds) Cytokines as potential therapeutic targets for inflammatory skin diseases. Ernst Schering Research Foundation Workshop, vol 56. Springer, Berlin, Heidelberg, pp 161–186. https://doi.org/10.1007/3-540-37673-9_10

    Chapter  Google Scholar 

  2. Bao L, Alexander JB, Shi VY, Mohan GC, Chan LS (2014) Interleukin-4 up-regulation of epidermal interleukin-19 expression in keratinocytes involves the binding of signal transducer and activator of transcription 6 (Stat6) to the imperfect Stat6 sites. Immunology 143:601–608. https://doi.org/10.1111/imm.12339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bao L, Alexander JB, Zhang H, Shen K, Chan LS (2016) Interleukin-4 downregulation of involucrin expression in human epidermal keratinocytes involves stat6 sequestration of the coactivator CREB-binding protein. J Interferon Cytokine Res 36:374–381. https://doi.org/10.1089/jir.2015.0056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bao L, Chau C, Bao J, Tsoukas MM, Chan LS (2018) IL-4 dysregulates microRNAs involved in inflammation, angiogenesis and apoptosis in epidermal keratinocytes. Microbiol Immunol 62:732–736. https://doi.org/10.1111/1348-0421.12650

    Article  CAS  PubMed  Google Scholar 

  5. Bao L, Mohan GC, Alexander JB, Doo C, Shen K, Bao J, Chan LS (2017) A molecular mechanism for IL-4 suppression of loricrin transcription in epidermal keratinocytes: implication for atopic dermatitis pathogenesis. Innate Immun 23:641–647. https://doi.org/10.1177/1753425917732823

    Article  CAS  PubMed  Google Scholar 

  6. Bao L, Zhang H, Mohan GC, Shen K, Chan LS (2016) Differential expression of inflammation-related genes in IL-4 transgenic mice before and after the onset of atopic dermatitis skin lesions. Mol Cell Probes 30:30–38. https://doi.org/10.1016/j.mcp.2015.11.001

    Article  CAS  PubMed  Google Scholar 

  7. Barry ZR, Kynast RW, Stinson WA, Fox DA, Amin MA, Rabquer BJ (2016) miR429 is Upregulated in inflammatory monocytes and regulates monocyte migration. Faseb J. https://doi.org/10.1096/fasebj.30.1_supplement.1028.13

    Article  Google Scholar 

  8. Biton M, Levin A, Slyper M, Alkalay I, Horwitz E, Mor H, Kredo-Russo S, Avnit-Sagi T, Cojocaru G, Zreik F, Bentwich Z, Poy MN, Artis D, Walker MD, Hornstein E, Pikarsky E, Ben-Neriah Y (2011) Epithelial microRNAs regulate gut mucosal immunity via epithelium-T cell crosstalk. Nat Immunol 12:239-U275. https://doi.org/10.1038/ni.1994

    Article  CAS  PubMed  Google Scholar 

  9. Chan LS, Robinson N, Xu L (2001) Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J Invest Dermatol 117:977–983. https://doi.org/10.1046/j.0022-202x.2001.01484.x

    Article  CAS  PubMed  Google Scholar 

  10. Chiba Y, Tanabe M, Goto K, Sakai H, Misawa M (2009) Down-regulation of miR-133a contributes to up-regulation of Rhoa in bronchial smooth muscle cells. Am J Respir Crit Care Med 180:713–719. https://doi.org/10.1164/rccm.200903-0325OC

    Article  CAS  PubMed  Google Scholar 

  11. Chuang TD, Ho M, Khorram O (2015) The regulatory function of miR-200c on inflammatory and cell-cycle associated genes in SK-LMS-1, a leiomyosarcoma cell line. Reprod Sci 22:563–571. https://doi.org/10.1177/1933719114553450

    Article  CAS  PubMed  Google Scholar 

  12. da Silva W, dos Santos RA, Moraes KC (2016) Mir-351-5p contributes to the establishment of a pro-inflammatory environment in the H9c2 cell line by repressing PTEN expression. Mol Cell Biochem 411:363–371. https://doi.org/10.1007/s11010-015-2598-5

    Article  CAS  PubMed  Google Scholar 

  13. Gandhi NA, Pirozzi G, Graham NMH (2017) Commonality of the IL-4/IL-13 pathway in atopic diseases. Expert Rev Clin Immunol 13:425–437. https://doi.org/10.1080/1744666X.2017.1298443

    Article  CAS  PubMed  Google Scholar 

  14. Guidi R, Wedeles CJ, Wilson MS (2020) ncRNAs in type-2 immunity. Non-Coding RNA 6:10 (ARTN103390/ncrna6010010)

    Article  CAS  Google Scholar 

  15. Hu J, Zhai C, Hu J, Li Z, Fei H, Wang Z, Fan W (2017) MiR-23a inhibited IL-17-mediated proinflammatory mediators expression via targeting IKKalpha in articular chondrocytes. Int Immunopharmacol 43:1–6. https://doi.org/10.1016/j.intimp.2016.11.031

    Article  CAS  PubMed  Google Scholar 

  16. Hu YW, Zhao JY, Li SF, Huang JL, Qiu YR, Ma X, Wu SG, Chen ZP, Hu YR, Yang JY, Wang YC, Gao JJ, Sha YH, Zheng L, Wang Q (2015) RP5-833A20.1/miR-382-5p/NFIA-dependent signal transduction pathway contributes to the regulation of cholesterol homeostasis and inflammatory reaction. Arterioscler Thromb Vasc Biol 35:87–101. https://doi.org/10.1161/ATVBAHA.114.304296

    Article  CAS  PubMed  Google Scholar 

  17. Huang J, Zhu L, Qiu C, Xu X, Zhang L, Ding X, Liao Q, Xu J, Zhang X (2017) MicroRNA miR-126-5p enhances the inflammatory responses of monocytes to lipopolysaccharide stimulation by suppressing cylindromatosis in chronic HIV-1 infection. J Virol. https://doi.org/10.1128/JVI.02048-16

    Article  PubMed  PubMed Central  Google Scholar 

  18. Jeong JH, Park SJ, Dickinson SI, Luo JL (2017) A constitutive intrinsic inflammatory signaling circuit composed of miR-196b, Meis2, PPP3CC, and p65 drives prostate cancer castration resistance. Mol Cell 65:154–167. https://doi.org/10.1016/j.molcel.2016.11.034

    Article  CAS  PubMed  Google Scholar 

  19. Jin HL, He R, Oyoshi M, Geha RS (2009) Animal models of atopic dermatitis. J Invest Dermatol 129:31–40. https://doi.org/10.1038/jid.2008.106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu Z, Jiang J, Yang Q, Xiong Y, Zou D, Yang C, Xu J, Zhan H (2016) MicroRNA-682-mediated downregulation of PTEN in intestinal epithelial cells ameliorates intestinal ischemia-reperfusion injury. Cell Death Dis 7:e2210. https://doi.org/10.1038/cddis.2016.84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lu TX, Hartner J, Lim EJ, Fabry V, Mingler MK, Cole ET, Orkin SH, Aronow BJ, Rothenberg ME (2011) MicroRNA-21 limits in vivo immune response-mediated activation of the IL-12/IFN-gamma pathway, Th1 polarization, and the severity of delayed-type hypersensitivity. J Immunol 187:3362–3373. https://doi.org/10.4049/jimmunol.1101235

    Article  CAS  PubMed  Google Scholar 

  22. Mun J, Tam C, Chan G, Kim JH, Evans D, Fleiszig S (2013) MicroRNA-762 is upregulated in human corneal epithelial cells in response to tear fluid and pseudomonas aeruginosa antigens and negatively regulates the expression of host defense genes encoding RNase7 and ST2. PLoS ONE 8:e57850. https://doi.org/10.1371/journal.pone.0057850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Otsuka A, Nomura T, Rerknimitr P, Seidel JA, Honda T, Kabashima K (2017) The interplay between genetic and environmental factors in the pathogenesis of atopic dermatitis. Immunol Rev 278:246–262. https://doi.org/10.1111/imr.12545

    Article  CAS  PubMed  Google Scholar 

  24. Shao Y, Lv C, Wu C, Zhou Y, Wang Q (2016) Mir-217 promotes inflammation and fibrosis in high glucose cultured rat glomerular mesangial cells via Sirt1/HIF-1alpha signaling pathway. Diabetes Metab Res Rev 32:534–543. https://doi.org/10.1002/dmrr.2788

    Article  CAS  PubMed  Google Scholar 

  25. Shi VY, Bao L, Chan LS (2012) Inflammation-driven dermal lymphangiogenesis in atopic dermatitis is associated with CD11b+ macrophage recruitment and VEGF-C up-regulation in the IL-4-transgenic mouse model. Microcirculation 19:567–579. https://doi.org/10.1111/j.1549-8719.2012.00189.x

    Article  CAS  PubMed  Google Scholar 

  26. Simpson LJ, Patel S, Bhakta NR, Choy DF, Brightbill HD, Ren X, Wang YL, Pua HH, Baumjohann D, Montoya MM, Panduro M, Remedios KA, Huang XZ, Fahy JV, Arron JR, Woodruff PG, Ansel KM (2014) A microRNA upregulated in asthma airway T cells promotes T(H)2 cytokine production. Nat Immunol 15:1162–1170. https://doi.org/10.1038/ni.3026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Song L, Lin C, Gong H, Wang C, Liu L, Wu J, Tao S, Hu B, Cheng SY, Li M, Li J (2013) miR-486 sustains NF-kappaB activity by disrupting multiple NF-kappaB-negative feedback loops. Cell Res 23:274–289. https://doi.org/10.1038/cr.2012.174

    Article  CAS  PubMed  Google Scholar 

  28. Su S, Zhao Q, He C, Huang D, Liu J, Chen F, Chen J, Liao JY, Cui X, Zeng Y, Yao H, Su F, Liu Q, Jiang S, Song E (2015) miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program. Nat Commun 6:8523. https://doi.org/10.1038/ncomms9523

    Article  CAS  PubMed  Google Scholar 

  29. Tamai K, Kaneda Y, Nakamura H, Aoki M, Morishita R, Hashimoto K, Morita A, Katayama I, Hanada K (2005) NFkappaB decoy DNA for treatment of atopic dermatitis. Nihon Rinsho 63(Suppl 12):659–663

    PubMed  Google Scholar 

  30. Tenda Y, Yamashita M, Kimura MY, Hasegawa A, Shimizu C, Kitajima M, Onodera A, Suzuki A, Seki N, Nakayama T (2006) Hyperresponsive TH2 cells with enhanced nuclear factor-kappa B activation induce atopic dermatitis-like skin lesions in Nishiki-nezumi Cinnamon/Nagoya mice. J Allergy Clin Immunol 118:725–733. https://doi.org/10.1016/j.jaci.2006.05.024

    Article  CAS  PubMed  Google Scholar 

  31. Tokuhira N, Kitagishi Y, Suzuki M, Minami A, Nakanishi A, Ono Y, Kobayashi K, Matsuda S, Ogura Y (2015) PI3K/AKT/PTEN pathway as a target for Crohn’s disease therapy. Int J Mol Med 35:10–16. https://doi.org/10.3892/ijmm.2014.1981

    Article  CAS  PubMed  Google Scholar 

  32. Wang Y, Weng H, Song JF, Deng YH, Li S, Liu HB (2017) Activation of the HMGB1-TLR4-NF-kappa B pathway may occur in patients with atopic eczema. Mol Med Rep 16:2714–2720. https://doi.org/10.3892/mmr.2017.6942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wardyn JD, Ponsford AH, Sanderson CM (2015) Dissecting molecular cross-talk between Nrf2 and NF-kappa B response pathways. Biochem Soc T 43:621–626. https://doi.org/10.1042/Bst20150014

    Article  CAS  Google Scholar 

  34. Wei Y, Nazari-Jahantigh M, Chan L, Zhu M, Heyll K, Corbalan-Campos J, Hartmann P, Thiemann A, Weber C, Schober A (2013) The microRNA-342-5p fosters inflammatory macrophage activation through an Akt1- and microRNA-155-dependent pathway during atherosclerosis. Circulation 127:1609–1619. https://doi.org/10.1161/CIRCULATIONAHA.112.000736

    Article  CAS  PubMed  Google Scholar 

  35. Xiaokelaiti H, Zhi X, Yusufujiang Y, Aikebaier A (2016) MiR-128-3p regulates inflammatory response in LPS-stimulated macrophages through the TLR4-NF-kappa B pathway. Int J Clin Exp Med 9:8005–8013

    CAS  Google Scholar 

  36. Xie W, Lu Q, Wang K, Lu J, Gu X, Zhu D, Liu F, Guo Z (2018) miR-34b-5p inhibition attenuates lung inflammation and apoptosis in an LPS-induced acute lung injury mouse model by targeting progranulin. J Cell Physiol 233:6615–6631. https://doi.org/10.1002/jcp.26274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang JC, Wu SC, Rau CS, Chen YC, Lu TH, Wu YC, Tzeng SL, Wu CJ, Hsieh CH (2015) TLR4/NF-kappaB-responsive microRNAs and their potential target genes: a mouse model of skeletal muscle ischemia-reperfusion injury. Biomed Res Int 2015:410721. https://doi.org/10.1155/2015/410721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yang Y, Wang Y, Liang Q, Yao L, Gu S, Bai X (2017) MiR-338-5p promotes inflammatory response of fibroblast-like synoviocytes in rheumatoid arthritis via targeting SPRY1. J Cell Biochem 118:2295–2301. https://doi.org/10.1002/jcb.25883

    Article  CAS  PubMed  Google Scholar 

  39. Yang Z, Zhong LN, Zhong SC, Xian RH, Yuan BQ (2015) miR-203 protects microglia mediated brain injury by regulating inflammatory responses via feedback to MyD88 in ischemia. Mol Immunol 65:293–301. https://doi.org/10.1016/j.molimm.2015.01.019

    Article  CAS  PubMed  Google Scholar 

  40. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW (2004) Modulation of NF-kappa B-dependent transcription and cell survival by the SIRT1 deacetylase. Embo J 23:2369–2380. https://doi.org/10.1038/sj.emboj.7600244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ying HJ, Kang YH, Zhang H, Zhao DJ, Xia JY, Lu Z, Wang HH, Xu F, Shi LY (2015) MiR-127 modulates macrophage polarization and promotes lung inflammation and injury by activating the JNK pathway. J Immunol 194:1239–1251. https://doi.org/10.4049/jimmunol.1402088

    Article  CAS  PubMed  Google Scholar 

  42. Yu X, Wang MF, Li LF, Zhang L, Chan MTV, Wu WKK (2020) MicroRNAs in atopic dermatitis: a systematic review. J Cell Mol Med 24:5966–5972. https://doi.org/10.1111/jcmm.15208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhao D, Zhuang N, Ding Y, Kang Y, Shi L (2016) MiR-221 activates the NF-kappaB pathway by targeting A20. Biochem Biophys Res Commun 472:11–18. https://doi.org/10.1016/j.bbrc.2015.11.009

    Article  CAS  PubMed  Google Scholar 

  44. Zhao JJ, Hu YW, Huang C, Ma X, Kang CM, Zhang Y, Guo FX, Lu JB, Xiu JC, Qiu YR, Sha YH, Gao JJ, Wang YC, Li P, Xu BM, Zheng L, Wang Q (2016) Dihydrocapsaicin suppresses proinflammatory cytokines expression by enhancing nuclear factor IA in a NF-kappaB-dependent manner. Arch Biochem Biophys 604:27–35. https://doi.org/10.1016/j.abb.2016.06.002

    Article  CAS  PubMed  Google Scholar 

  45. Zhao XJ, Yu HW, Yang YZ, Wu WY, Chen TY, Jia KK, Kang LL, Jiao RQ, Kong LD (2018) Polydatin prevents fructose-induced liver inflammation and lipid deposition through increasing miR-200a to regulate Keap1/Nrf2 pathway. Redox Biol 18:124–137. https://doi.org/10.1016/j.redox.2018.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhou Y, Yang Q, Xu H, Zhang J, Deng H, Gao H, Yang J, Zhao D, Liu F (2016) miRNA-221-3p enhances the secretion of interleukin-4 in mast cells through the phosphatase and tensin homolog/p38/nuclear factor-kappab pathway. PLoS ONE 11:e0148821. https://doi.org/10.1371/journal.pone.0148821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhu B, Ye J, Nie Y, Ashraf U, Zohaib A, Duan X, Fu ZF, Song Y, Chen H, Cao S (2015) MicroRNA-15b modulates Japanese encephalitis virus-mediated inflammation via targeting RNF125. J Immunol 195:2251–2262. https://doi.org/10.4049/jimmunol.1500370

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank the Albert H. and Mary Jane Slepyan Endowed Fellowship (L. Bao) for their support.

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Authors and Affiliations

  1. Department of Dermatology, UIC-Dermatology, RM 338, MC624, 808 S. Wood Street, Chicago, IL, 60612, USA

    Lei Bao, Angelina G. Chan, Kyle T. Amber & Maria M. Tsoukas

  2. Sequencing Core, Genome Research Division, Research Resources Center, Chicago, USA

    Cecilia S. Chau

  3. Research Informatics Core, Genome Research Division, Research Resources Center, University of Illinois, Chicago, USA

    Zhengdeng Lei, Hong Hu & Mark Maienschein-Cline

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  1. Lei Bao
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403_2020_2176_MOESM1_ESM.pdf

Supplementary file1 (PDF 1734 KB) Supplemental Figure 1. Top network identified in the dysregulated microRNAs before the onset of skin lesions in IL-4 Tg mice. Network analysis was performed on the differentially expressed microRNAs using ingenuity pathway analysis (IPA) software (Qiagen). The detailed IPA legend can be found at http://qiagen.force.com/KnowledgeBase/articles/Basic_Technical_Q_A/Legend.

403_2020_2176_MOESM2_ESM.pdf

Supplementary file2 (PDF 2567 KB) Supplemental Figure 2. Top networks identified in the dysregulated microRNAs after the onset of skin lesions in IL-4 Tg mice.

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Bao, L., Chau, C.S., Lei, Z. et al. Dysregulated microRNA expression in IL-4 transgenic mice, an animal model of atopic dermatitis. Arch Dermatol Res 313, 837–846 (2021). https://doi.org/10.1007/s00403-020-02176-w

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