IL-13Rα2 Has a Protective Role in a Mouse Model of Cutaneous Inflammation

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2010 Oct 26

PMID 20971924

Citations 23

Authors

Umasundari Sivaprasad

Manoj R Warrier

Aaron M Gibson

Weiguo Chen

Yasuhiro Tabata

Stacey A Bass

Marc E Rothenberg

Gurjit K Khurana Hershey

Affiliations

Soon will be listed here.

Abstract

IL-13 is expressed in lesions of atopic dermatitis (AD) and has been associated with increased disease severity. IL-13 has two cognate receptors: IL-13Rα1 and IL-13Rα2. Although IL-13Rα2 expression is known to be induced in response to IL-13 in keratinocytes, its function in AD has never been evaluated. We characterized the loss of skin barrier function and the development of cutaneous inflammation in IL-13Rα2-null versus wild-type BALB/c mice following an epicutaneous allergen-sensitization/challenge model that shares similarities with human AD. Mice lacking IL-13Rα2 had significantly increased transepidermal water loss, cutaneous inflammation, peripheral eosinophilia, and IgG1 and IgE levels compared with wild-type mice. The rate of resolution of the cutaneous inflammation was not significantly altered in the IL-13Rα2-null mice. IL-13 induced expression of IL-13Rα2 in keratinocyte cell lines and primary human keratinocytes. Depletion of IL-13Rα2 in a keratinocyte cell line resulted in increased STAT6 signaling in response to IL-13. In conclusion, IL-13Rα2 serves a protective role in the pathogenesis of allergic inflammation and loss of skin barrier function in a mouse model of AD, suggesting that it may be an important endogenous regulator of IL-13-induced cutaneous inflammation in humans.

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References

Brandt E, Rothenberg M . Eosinophil levels in mice are significantly higher in small blood vessels than in large blood vessels. J Allergy Clin Immunol. 2001; 108(1):142-3. DOI: 10.1067/mai.2001.116121. View

Rahaman S, Sharma P, Harbor P, Aman M, Vogelbaum M, Haque S . IL-13R(alpha)2, a decoy receptor for IL-13 acts as an inhibitor of IL-4-dependent signal transduction in glioblastoma cells. Cancer Res. 2002; 62(4):1103-9. View

Miloux B, Laurent P, Bonnin O, Lupker J, Caput D, Vita N . Cloning of the human IL-13R alpha1 chain and reconstitution with the IL4R alpha of a functional IL-4/IL-13 receptor complex. FEBS Lett. 1997; 401(2-3):163-6. DOI: 10.1016/s0014-5793(96)01462-7. View

Lee J, McGarry M, Farmer S, Denzler K, Larson K, Carrigan P . Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma. J Exp Med. 1997; 185(12):2143-56. PMC: 2196351. DOI: 10.1084/jem.185.12.2143. View

Hilton D, Zhang J, Metcalf D, Alexander W, Nicola N, Willson T . Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor. Proc Natl Acad Sci U S A. 1996; 93(1):497-501. PMC: 40265. DOI: 10.1073/pnas.93.1.497. View

Zheng T, Oh M, Oh S, Schroeder J, Glick A, Zhu Z . Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol. 2008; 129(3):742-51. PMC: 4356214. DOI: 10.1038/jid.2008.295. View

McKenzie A, Li X, Largaespada D, Sato A, Kaneda A, Zurawski S . Structural comparison and chromosomal localization of the human and mouse IL-13 genes. J Immunol. 1993; 150(12):5436-44. View

Lee C, Homer R, Zhu Z, Lanone S, Wang X, Koteliansky V . Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med. 2001; 194(6):809-21. PMC: 2195954. DOI: 10.1084/jem.194.6.809. View

La Grutta S, Richiusa P, Pizzolanti G, Mattina A, Pajno G, Citarrella R . CD4(+)IL-13(+) cells in peripheral blood well correlates with the severity of atopic dermatitis in children. Allergy. 2005; 60(3):391-5. DOI: 10.1111/j.1398-9995.2005.00733.x. View

10.

Esche C, Benedetto A, Beck L . Keratinocytes in atopic dermatitis: inflammatory signals. Curr Allergy Asthma Rep. 2004; 4(4):276-84. DOI: 10.1007/s11882-004-0071-8. View

11.

Khodoun M, Lewis C, Lewis C, Yang J, Orekov T, Potter C . Differences in expression, affinity, and function of soluble (s)IL-4Ralpha and sIL-13Ralpha2 suggest opposite effects on allergic responses. J Immunol. 2007; 179(10):6429-38. DOI: 10.4049/jimmunol.179.10.6429. View

12.

Zuo L, Fulkerson P, Finkelman F, Mingler M, Fischetti C, Blanchard C . IL-13 induces esophageal remodeling and gene expression by an eosinophil-independent, IL-13R alpha 2-inhibited pathway. J Immunol. 2010; 185(1):660-9. PMC: 3746758. DOI: 10.4049/jimmunol.1000471. View

13.

Purwar R, Werfel T, Wittmann M . Regulation of IL-13 receptors in human keratinocytes. J Invest Dermatol. 2007; 127(5):1271-4. DOI: 10.1038/sj.jid.5700687. View

14.

Daines M, Khurana Hershey G . A novel mechanism by which interferon-gamma can regulate interleukin (IL)-13 responses. Evidence for intracellular stores of IL-13 receptor alpha -2 and their rapid mobilization by interferon-gamma. J Biol Chem. 2002; 277(12):10387-93. DOI: 10.1074/jbc.M108109200. View

15.

Wood N, Whitters M, Jacobson B, Witek J, Sypek J, Kasaian M . Enhanced interleukin (IL)-13 responses in mice lacking IL-13 receptor alpha 2. J Exp Med. 2003; 197(6):703-9. PMC: 2193851. DOI: 10.1084/jem.20020906. View

16.

Lu Z, Park D, Lee K, Ryu J, Bhak J, Shi L . Profiling the dysregulated genes of keratinocytes in atopic dermatitis patients: cDNA microarray and interactomic analyses. J Dermatol Sci. 2009; 54(2):126-9. DOI: 10.1016/j.jdermsci.2008.12.006. View

17.

Ellis C, Drake L, Prendergast M, Abramovits W, Boguniewicz M, Daniel C . Cost of atopic dermatitis and eczema in the United States. J Am Acad Dermatol. 2002; 46(3):361-70. DOI: 10.1067/mjd.2002.120528. View

18.

Andrews A, Nasir T, Bucchieri F, Holloway J, Holgate S, Davies D . IL-13 receptor alpha 2: a regulator of IL-13 and IL-4 signal transduction in primary human fibroblasts. J Allergy Clin Immunol. 2006; 118(4):858-65. DOI: 10.1016/j.jaci.2006.06.041. View

19.

Leung D, Boguniewicz M, Howell M, Nomura I, Hamid Q . New insights into atopic dermatitis. J Clin Invest. 2004; 113(5):651-7. PMC: 351324. DOI: 10.1172/JCI21060. View

20.

Fichtner-Feigl S, Strober W, Kawakami K, Puri R, Kitani A . IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med. 2005; 12(1):99-106. DOI: 10.1038/nm1332. View