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Intrauterine growth restriction induces skin inflammation, increases TSLP and impairs epidermal barrier function

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Abstract

Intrauterine growth restriction (IUGR) and low birth weight are risk factors for childhood asthma. Atopic march describes the progression from early dermatitis to asthma during life. Since inflammatory signaling is linked to increased airway resistance and lung remodeling in rats after IUGR, we queried if these findings are related to skin inflammatory response. Firstly, we induced IUGR in Wistar rats by isocaloric protein restriction during gestation. IUGR rats showed lower body weight at postnatal day 1 (P1), catch-up growth at P21, and similar body weight like controls at P90. At P1 and P90, mRNA of inflammatory as well as fibrotic markers and number of skin immune cells (macrophages) were increased after IUGR. Skin thymic stromal lymphopoietin (TSLP) mRNA at P1 and serum TSLP at P1 and P21 were elevated in IUGR. Moreover, IUGR impaired transepidermal water loss at P21 and P90. IUGR induced higher. Secondly, the increase of TEWL after Oxazolone treatment as a model of atopic dermatitis (AD) was greater in IUGR than in Co. Our data demonstrate an early inflammatory skin response, which is linked to persistent macrophage infiltration in the skin and impaired epidermal barrier function after IUGR. These findings coupled with elevated TSLP could underlie atopic diseases in rats after IUGR.

Key messages

• The present study shows that IUGR increases macrophage infiltration and induces an inflammatory and fibrotic gene expression pattern in the skin of newborn rats.

• Early postnatal inflammatory response in the skin after IUGR is followed by impaired epidermal barrier function later in life.

• IUGR aggravates transepidermal water loss in an experimental atopic dermatitis model, possibly through elevated TSLP in skin and serum.

• Early anti-inflammatory treatment and targeting TSLP signaling could offer novel avenues for early prevention of atopic disorders and late asthma in high-risk infants.

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Abbreviations

Ccl2 :

CC-chemokine ligand 2

Col3 :

Collagen 3

Col1A1 :

Collagen 1α1

Cxcr3 :

CXC-motive-chemokine receptor 3

Fap:

fibroblast activation protein

Il4 :

Interleukin 4

Il5 :

Interleukin 5

Il6 :

Interleukin 6

IL7rα :

Interleukin 7 α receptor

Il10 :

Interleukin 4

Il13 :

Interleukin 13

Gapdh :

Glycerinaldehyd-3-phosphat-dehydrogenase ()

Serpine1:

Plasminogen activator inhibitor-1

Tslp :

Thymic stromal lymphopoietin

Tslprα :

Thymic stromal lymphopoietin α receptor

References

  1. Asher MI, Montefort S, Bjorksten B, Lai CK, Strachan DP, Weiland SK, Williams H, Group IPTS (2006) Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC phases one and three repeat multicountry cross-sectional surveys. Lancet 368(9537):733–743

    PubMed  Google Scholar 

  2. Kamer B, Pasowska R, Dolka E, Blomberg A, Rotsztejn H (2013) Prevalence of atopic dermatitis in infants during the first six months of life: authors' observations. Postepy Dermatol Alergol 30(5):277–281

    PubMed  PubMed Central  Google Scholar 

  3. Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD (2018) Atopic dermatitis. Nat Rev Dis Primers 4(1):1

    PubMed  Google Scholar 

  4. Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M, Guy RH, Macgowan AL, Tazi-Ahnini R, Ward SJ (2009) Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 129(8):1892–1908

    PubMed  CAS  Google Scholar 

  5. Spergel JM, Paller AS (2003) Atopic dermatitis and the atopic march. J Allergy Clin Immunol 112(6 Suppl):S118–S127

    PubMed  Google Scholar 

  6. Hales CN, Barker DJ (2001) The thrifty phenotype hypothesis. Br Med Bull 60:5–20

    PubMed  CAS  Google Scholar 

  7. Plagemann A (2005) Perinatal programming and functional teratogenesis: impact on body weight regulation and obesity. Physiol Behav 86(5):661–668

    PubMed  CAS  Google Scholar 

  8. Sonnenschein-van der Voort AM, Jaddoe VW, Raat H, Moll HA, Hofman A, de Jongste JC, Duijts L (2012) Fetal and infant growth and asthma symptoms in preschool children: the generation R study. Am J Respir Crit Care Med 185(7):731–737

    PubMed  Google Scholar 

  9. Alejandre Alcazar MA, Morty RE, Lendzian L, Vohlen C, Oestreicher I, Plank C, Schneider H, Dotsch J (2011) Inhibition of TGF-beta signaling and decreased apoptosis in IUGR-associated lung disease in rats. PLoS One 6(10):e26371

    PubMed  PubMed Central  Google Scholar 

  10. Alejandre Alcazar MA, Ostreicher I, Appel S, Rother E, Vohlen C, Plank C, Dotsch J (2012) Developmental regulation of inflammatory cytokine-mediated Stat3 signaling: the missing link between intrauterine growth restriction and pulmonary dysfunction? J Mol Med 90(8):945–957

    PubMed  Google Scholar 

  11. Alcazar MA, Dinger K, Rother E, Ostreicher I, Vohlen C, Plank C, Dotsch J (2014) Prevention of early postnatal hyperalimentation protects against activation of transforming growth factor-beta/bone morphogenetic protein and interleukin-6 signaling in rat lungs after intrauterine growth restriction. J Nutr 144(12):1943–1951

    PubMed  CAS  Google Scholar 

  12. Thangaratnarajah C, Dinger K, Vohlen C, Klaudt C, Nawabi J, Lopez Garcia E, Kwapiszewska G, Dobner J, Nuesken KD, van Koningsbruggen-Rietschel S, von Hoersten S, Dotsch J, Alejandre Alcazar MA (2017) Novel role of NPY in neuro-immune interaction and lung growth after intrauterine growth restriction. Am J Physiol Lung Cell Mol Physiol 00432:02016

    Google Scholar 

  13. Bonifati C, Carducci M, Cordiali Fei P, Trento E, Sacerdoti G, Fazio M, Ameglio F (1994) Correlated increases of tumour necrosis factor-alpha, interleukin-6 and granulocyte monocyte-colony stimulating factor levels in suction blister fluids and sera of psoriatic patients--relationships with disease severity. Clin Exp Dermatol 19(5):383–387

    PubMed  CAS  Google Scholar 

  14. Toshitani A, Ansel JC, Chan SC, Li SH, Hanifin JM (1993) Increased interleukin 6 production by T cells derived from patients with atopic dermatitis. J Invest Dermatol 100(3):299–304

    PubMed  CAS  Google Scholar 

  15. Esparza-Gordillo J, Schaarschmidt H, Liang L, Cookson W, Bauerfeind A, Lee-Kirsch MA, Nemat K, Henderson J, Paternoster L, Harper JI, Mangold E, Nothen MM, Ruschendorf F, Kerscher T, Marenholz I, Matanovic A, Lau S, Keil T, Bauer CP, Kurek M, Ciechanowicz A, Macek M, Franke A, Kabesch M, Hubner N, Abecasis G, Weidinger S, Moffatt M, Lee YA (2013) A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis. J Allergy Clin Immunol 132(2):371–377

    PubMed  CAS  Google Scholar 

  16. Sawamura D, Meng X, Ina S, Sato M, Tamai K, Hanada K, Hashimoto I (1998) Induction of keratinocyte proliferation and lymphocytic infiltration by in vivo introduction of the IL-6 gene into keratinocytes and possibility of keratinocyte gene therapy for inflammatory skin diseases using IL-6 mutant genes. J Immunol 161(10):5633–5639

    PubMed  CAS  Google Scholar 

  17. Lin ZQ, Kondo T, Ishida Y, Takayasu T, Mukaida N (2003) Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice. J Leukoc Biol 73(6):713–721

    PubMed  CAS  Google Scholar 

  18. Morjaria JB, Babu KS, Vijayanand P, Chauhan AJ, Davies DE, Holgate ST (2011) Sputum IL-6 concentrations in severe asthma and its relationship with FEV1. Thorax 66(6):537

    PubMed  CAS  Google Scholar 

  19. Steffensen FH, Sorensen HT, Gillman MW, Rothman KJ, Sabroe S, Fischer P, Olsen J (2000) Low birth weight and preterm delivery as risk factors for asthma and atopic dermatitis in young adult males. Epidemiology 11(2):185–188

    PubMed  CAS  Google Scholar 

  20. Logan CA, Weiss JM, Reister F, Rothenbacher D, Genuneit J (2018) Fetal growth and incidence of atopic dermatitis in early childhood: results of the Ulm SPATZ health study. Sci Rep 8(1):8041

    PubMed  PubMed Central  Google Scholar 

  21. Segre JA (2006) Epidermal barrier formation and recovery in skin disorders. J Clin Invest 116(5):1150–1158

    PubMed  PubMed Central  CAS  Google Scholar 

  22. Lansdown AB (1978) Epidermal differentiation in normal and growth-retarded infants: studies in two animal models and in human babies. Br J Dermatol 99(2):139–146

    PubMed  CAS  Google Scholar 

  23. Hoath SB, Pickens WL, Sells SF, Boissy RE (1990) Epidermal development in the growth retarded fetal rat. J Dev Physiol 13(1):41–50

    PubMed  CAS  Google Scholar 

  24. Nakano Y (2004) Stress-induced modulation of skin immune function: two types of antigen-presenting cells in the epidermis are differentially regulated by chronic stress. Br J Dermatol 151(1):50–64

    PubMed  CAS  Google Scholar 

  25. Man MQ, Hatano Y, Lee SH, Man M, Chang S, Feingold KR, Leung DY, Holleran W, Uchida Y, Elias PM (2008) Characterization of a hapten-induced, murine model with multiple features of atopic dermatitis: structural, immunologic, and biochemical changes following single versus multiple oxazolone challenges. J Invest Dermatol 128(1):79–86

    PubMed  CAS  Google Scholar 

  26. Barel AO, Clarys P (1995) Study of the stratum corneum barrier function by transepidermal water loss measurements: comparison between two commercial instruments: Evaporimeter and Tewameter. Skin Pharmacol 8(4):186–195

    PubMed  CAS  Google Scholar 

  27. Mohr J, Voggel J, Vohlen C, Dinger K, Dafinger C, Fink G, Gobel H, Liebau MC, Dotsch J, Alejandre Alcazar MA (2019) IL-6/Smad2 signaling mediates acute kidney injury and regeneration in a murine model of neonatal hyperoxia. FASEB J:fj201801875RR. https://doi.org/10.1096/fj.201801875RR

    PubMed  CAS  Google Scholar 

  28. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9(7):676–682

    CAS  Google Scholar 

  29. Ying S, O'Connor B, Ratoff J, Meng Q, Fang C, Cousins D, Zhang G, Gu S, Gao Z, Shamji B, Edwards MJ, Lee TH, Corrigan CJ (2008) Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J Immunol 181(4):2790–2798

    PubMed  CAS  Google Scholar 

  30. Panduru M, Salavastru CM, Panduru NM, Tiplica GS (2014) Birth weight and atopic dermatitis: systematic review and meta-analyis. Acta Dermatovenerol Croat 22(2):91–96

    PubMed  Google Scholar 

  31. Kasraie S, Werfel T (2013) Role of macrophages in the pathogenesis of atopic dermatitis. Mediat Inflamm 2013:942375

    Google Scholar 

  32. Li G, Jin F, Du J, He Q, Yang B, Luo P (2019) Macrophage-secreted TSLP and MMP9 promote bleomycin-induced pulmonary fibrosis. Toxicol Appl Pharmacol 366:10–16

    PubMed  CAS  Google Scholar 

  33. Chisaka T, Mogi M, Nakaoka H, Kan-No H, Tsukuda K, Wang XL, Bai HY, Shan BS, Kukida M, Iwanami J, Higaki T, Ishii E, Horiuchi M (2016) Low-protein diet-induced fetal growth restriction leads to exaggerated proliferative response to vascular injury in postnatal life. Am J Hypertens 29(1):54–62

    PubMed  CAS  Google Scholar 

  34. Plank C, Ostreicher I, Hartner A, Marek I, Struwe FG, Amann K, Hilgers KF, Rascher W, Dotsch J (2006) Intrauterine growth retardation aggravates the course of acute mesangioproliferative glomerulonephritis in the rat. Kidney Int 70(11):1974–1982

    PubMed  CAS  Google Scholar 

  35. Demehri S, Morimoto M, Holtzman MJ, Kopan R (2009) Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. PLoS Biol 7(5):e1000067

    PubMed  PubMed Central  Google Scholar 

  36. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K, Gorman D, Zurawski S, Abrams J, Menon S, McClanahan T, de Waal-Malefyt RR, Bazan F, Kastelein RA, Liu YJ (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3(7):673–680

    PubMed  CAS  Google Scholar 

  37. Redhu NS, Gounni AS (2012) Function and mechanisms of TSLP/TSLPR complex in asthma and COPD. Clin Exp Allergy 42(7):994–1005

    PubMed  CAS  Google Scholar 

  38. Kim J, Kim BE, Lee J, Han Y, Jun HY, Kim H, Choi J, Leung DYM, Ahn K (2016) Epidermal thymic stromal lymphopoietin predicts the development of atopic dermatitis during infancy. J Allergy Clin Immunol 137(4):1282–1285 e1284

    PubMed  CAS  Google Scholar 

  39. Leyva-Castillo JM, Hener P, Jiang H, Li M (2013) TSLP produced by keratinocytes promotes allergen sensitization through skin and thereby triggers atopic march in mice. J Invest Dermatol 133(1):154–163

    PubMed  CAS  Google Scholar 

  40. Zhou B, Comeau MR, De Smedt T, Liggitt HD, Dahl ME, Lewis DB, Gyarmati D, Aye T, Campbell DJ, Ziegler SF (2005) Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol 6(10):1047–1053

    PubMed  CAS  Google Scholar 

  41. Han H, Headley MB, Xu W, Comeau MR, Zhou B, Ziegler SF (2013) Thymic stromal lymphopoietin amplifies the differentiation of alternatively activated macrophages. J Immunol 190(3):904–912

    PubMed  CAS  Google Scholar 

  42. Liu D, Guo M, Zhou P, Xiao J, Ji X (2019) TSLP promote M2 macrophages polarization and cardiac healing after myocardial infarction. Biochem Biophys Res Commun 516(2):437–444

    PubMed  CAS  Google Scholar 

  43. Al-Shami A, Spolski R, Kelly J, Keane-Myers A, Leonard WJ (2005) A role for TSLP in the development of inflammation in an asthma model. J Exp Med 202(6):829–839

    PubMed  PubMed Central  CAS  Google Scholar 

  44. Cianferoni A, Spergel J (2014) The importance of TSLP in allergic disease and its role as a potential therapeutic target. Expert Rev Clin Immunol 10(11):1463–1474

    PubMed  PubMed Central  CAS  Google Scholar 

  45. Chen ZG, Meng P, Li HT, Li M, Yang LF, Yan Y, Li YT, Zou XL, Wang DY, Zhang TT (2017) Thymic stromal lymphopoietin contribution to the recruitment of circulating fibrocytes to the lung in a mouse model of chronic allergic asthma. J Asthma:1–9. https://doi.org/10.1080/02770903.2017.1386213

    PubMed  Google Scholar 

  46. Hu Y, Dong H, Zou M, Huang C, Luo L, Yu C, Chen J, Xie Z, Zhao H, Le Y, Zou F, Liu L, Cai S (2017) TSLP signaling blocking alleviates E-cadherin dysfunction of airway epithelium in a HDM-induced asthma model. Cell Immunol 315:56–63

    PubMed  CAS  Google Scholar 

  47. Cheng Z, Wang X, Dai LL, Jia LQ, Jing XG, Liu Y, Wang H, Li PF, An L, Liu M (2018) Thymic stromal Lymphopoietin signaling pathway inhibition attenuates airway inflammation and remodeling in rats with asthma. Cell Physiol Biochem 47(4):1482–1496

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank the essential input from all members of the Dötsch laboratory, Nüsken laboratory and Alcazar laboratory as well as the expert technical assistance of Annika Schmitz [Department of Dermatology, Center of Molecular Medicine Cologne (CMMC), CECAD, University Hospital Cologne, Germany].

Funding

This study was financially supported by Köln Fortune, Faculty of Medicine, University of Cologne [110/2010 (JD and MAAA)]; by Marga und Walter Boll Stiftung; Stiftung Oskar-Helene-Heim (VJ); Center of Molecular Medicine Cologne (CMMC) and SFB 829 A1, A5 and Z2 (CMN).

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Authors and Affiliations

  1. Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics, Experimental Pulmonology, University of Cologne, Kerpener Strasse 62, D-50937, Cologne, Germany

    Laura Polányi, Christina Vohlen, Vanessa Jentgen & Miguel A. Alejandre Alcazar

  2. Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

    Laura Polányi, Christina Vohlen, Tobias Kretschmer, Jörg Dötsch & Miguel A. Alejandre Alcazar

  3. Department of Dermatology, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

    Carien M. Niessen & Julia Stinn

  4. Center of Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

    Dharmesh Hirani & Miguel A. Alejandre Alcazar

  5. Pediatric Pulmonology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

    Silke V. Koningsbruggen-Rietschel

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  1. Laura Polányi
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  2. Carien M. Niessen
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  9. Jörg Dötsch
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  10. Miguel A. Alejandre Alcazar
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Contributions

L.P., C.N., J.D., and M.A.A.A. conceived and designed research; L.P., C.V., J.S., T.K., and M.A.A.A. performed experiments; L.P., T.K., D.H., and M.A.A.A. analyzed data; L.P., C.N., J.S., J.D., SvKR, and M.A.A.A. interpreted results of experiments; L.P., J.S., and M.A.A.A. prepared figures; L.P. and M.A.A.A. drafted manuscript; L.P., C.N., C.V., J.S., T.K., V.J., D.H., SvKR, J.D., and M.A.A.A. approved final version of manuscript; L.P. and M.A.A.A. edited and revised manuscript

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Correspondence to Miguel A. Alejandre Alcazar.

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Polányi, L., Niessen, C.M., Vohlen, C. et al. Intrauterine growth restriction induces skin inflammation, increases TSLP and impairs epidermal barrier function. J Mol Med 98, 279–289 (2020). https://doi.org/10.1007/s00109-019-01867-w

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