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

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

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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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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

Corresponding author

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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Keywords

  • Intrauterine growth restriction (IUGR)
  • Skin
  • Atopic diseases
  • Asthma
  • TSLP