Spontaneous atopic dermatitis due to immune dysregulation in mice lacking Adamts2 and 14.

[en] Since its first description, ADAMTS14 has been considered as an aminoprocollagen peptidase based on its high similarity with ADAMTS3 and ADAMTS2. As its importance for procollagen processing was never experimentally demonstrated in vivo, we generated Adamts14-deficient mice. They are healthy, fertile and display normal aminoprocollagen processing. They were further crossed with Adamts2-deficient mice to evaluate potential functional redundancies between these two highly related enzymes. Initial characterizations made on young Adamts2-Adamts14-deficient animals showed the same phenotype as that of Adamts2-deficient mice, with no further reduction of procollagen processing and no significant aggravation of the structural alterations of collagen fibrils. However, when evaluated at older age, Adamts2-Adamts14-deficient mice surprisingly displayed epidermal lesions, appearing in 2 month-old males and later in some females, and then worsening rapidly. Immunohistological evaluations of skin sections around the lesions revealed thickening of the epidermis, hypercellularity in the dermis and extensive infiltration by immune cells. Additional investigations, performed on young mice before the formation of the initial lesions, revealed that the primary cause of the phenotype was not related to alterations of the epidermal barrier but was rather the result of an abnormal activation and differentiation of T lymphocytes towards a Th1 profile. However, the primary molecular defect probably does not reside in the immune system itself since irradiated Adamts2-Adamts14-deficient mice grafted with WT immune cells still developed lesions. While originally created to better characterize the common and specific functions of ADAMTS2 and ADAMTS14 in extracellular matrix and connective tissues homeostasis, the Adamts2-Adamts14-deficient mice revealed an unexpected but significant role of ADAMTS in the regulation of immune system, possibly through a cross-talk involving mesenchymal cells and the TGFβ pathways.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Dupont, Laura ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire de Biologie des tissus conjonctifs

Ehx, Gregory

Chantry, Mathilde

Monseur, Christine ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire des tissus conjonctifs

Leduc, Cédric

Janssen, Lauriane

Cataldo, Didier ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement

Thiry, Marc ; Université de Liège - ULiège > Département des sciences de la vie > Biologie cellulaire

Jérôme, Christine ; Université de Liège - ULiège > Département de chimie (sciences) > Centre d'études et de rech. sur les macromolécules (CERM)

Thomassin, Jean-Michel ; Université de Liège - ULiège > Département de chimie (sciences) > Centre d'études et de rech. sur les macromolécules (CERM)

More authors (4 more)

Language :

English

Title :

Spontaneous atopic dermatitis due to immune dysregulation in mice lacking Adamts2 and 14.

Publication date :

2018

Journal title :

Matrix Biology

ISSN :

0945-053X

eISSN :

1569-1802

Publisher :

Elsevier, Netherlands

Volume :

Pages :

140-157

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 15 January 2019

Statistics

Number of views

121 (16 by ULiège)

Number of downloads

3 (3 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

Bibliography

Apte, S.S., Parks, W.C., Metalloproteinases: a parade of functions in matrix biology and an outlook for the future. Matrix Biol. 44–46 (May–Jul 2015), 1–6.
Apte, S.S., A disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif (ADAMTS) superfamily: functions and mechanisms. J. Biol. Chem. 284 (2009), 31493–31497.
Dubail, J., Apte, S.S., Insights on ADAMTS proteases and ADAMTS-like proteins from mammalian genetics. Matrix Biol. 44–46 (May–Jul 2015), 24–37.
Hopkins, D.R., Keles, S., Greenspan, D.S., The bone morphogenetic protein 1/Tolloid-like metalloproteinases. Matrix Biol. 26:7 (Sep 2007), 508–523.
Vadon-Le Goff, S., Hulmes, D.J., Moali, C., BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling. Matrix Biol. 44–46 (May–Jul 2015), 14–23.
Colige, A., Ruggiero, F., Vandenberghe, I., Dubail, J., Kesteloot, F., Van Beeumen, J., Beschin, A., Brys, L., Lapiere, C.M., Nusgens, B., Domains and maturation processes that regulate the activity of ADAMTS-2, a metalloproteinase cleaving the aminopropeptide of fibrillar procollagens types I–III and V. J. Biol. Chem. 280 (2005), 34397–34408.
Colige, A., Beschin, A., Samyn, B., Goebels, Y., Van Beeumen, J., Nusgens, B.V., Lapière, C.M., Characterization and partial amino acid sequencing of a 107-kDa procollagen I N-proteinase purified by affinity chromatography on immobilized type XIV collagen. J. Biol. Chem. 270:28 (1995), 16724–16730.
Colige, A., Li, S.W., Sieron, A.L., Nusgens, B.V., Prockop, D.J., Lapière, C.M., cDNA cloning and expression of bovine procollagen I N-proteinase: a new member of the superfamily of zinc-metalloproteinases with binding sites for cells and other matrix components. Proc. Natl. Acad. Sci. U. S. A. 94:6 (1997), 2374–2379.
Prockop, D.J., Sieron, A.L., Li, S.W., Procollagen N-proteinase and procollagen C-proteinase. Two unusual metalloproteinases that are essential for procollagen processing probably have important roles in development and cell signaling. Matrix Biol. 16:7 (1998), 399–408.
Fernandes, R.J., Hirohata, S., Engle, J.M., Colige, A., Cohn, D.H., Eyre, D.R., Apte, S.S., Procollagen II amino propeptide processing by ADAMTS-3. Insights on dermatosparaxis. J. Biol. Chem. 276 (2001), 31502–31509.
Colige, A., Sieron, A.L., Li, S.W., Schwarze, U., Petty, E., Wertelecki, W., Wilcox, W., Krakow, D., Cohn, D.H., Reardon, W., et al. Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene. Am. J. Hum. Genet. 65 (1999), 308–317.
Colige, A., Nuytinck, L., Hausser, I., van Essen, A.J., Thiry, M., Herens, C., Ades, L.C., Malfait, F., Paepe, A.D., Franck, P., et al. Novel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos syndrome (Type VIIC) and common polymorphisms in the ADAMTS2 gene. J. Invest. Dermatol. 123 (2004), 656–663.
Li, S.W., Arita, M., Fertala, A., Bao, Y., Kopen, G.C., Langsjo, T.K., Hyttinen, M.M., Helminen, H.J., Prockop, D.J., Transgenic mice with inactive alleles for procollagen N-proteinase (ADAMTS-2) develop fragile skin and male sterility. Biochem. J. 355 (2001), 271–278.
Colige, A., Vandenberghe, I., Thiry, M., Lambert, C.A., Van Beeumen, J., Li, S.W., Prockop, D.J., Lapiere, C.M., Nusgens, B.V., Cloning and characterization of ADAMTS-14, a novel ADAMTS displaying high homology with ADAMTS-2 and ADAMTS-3. J. Biol. Chem. 277 (2002), 5756–5766.
Le Goff, C., Somerville, R.P., Kesteloot, F., Powell, K., Birk, D.E., Colige, A.C., Apte, S.S., Regulation of procollagen amino-propeptide processing during mouse embryogenesis by specialization of homologous ADAMTS proteases: insights on collagen biosynthesis and dermatosparaxis. Development 133 (2006), 1587–1596.
Kesteloot, F., Desmoulière, A., Leclercq, I., Thiry, M., Arrese, J.E., Prockop, D.J., Lapière, C.M., Nusgens, B.V., Colige, A., ADAM metallopeptidase with thrombospondin type 1 motif 2 inactivation reduces the extent and stability of carbon tetrachloride-induced hepatic fibrosis in mice. Hepatology 46 (2007), 1620–1631.
Janssen, L., Dupont, L., Bekhouche, M., Noel, A., Leduc, C., Voz, M., Peers, B., Cataldo, D., Apte, S.S., Dubail, J., Colige, A., ADAMTS3 activity is mandatory for embryonic lymphangiogenesis and regulates placental angiogenesis. Angiogenesis 19 (2015), 53–65.
Jeltsch, M., Jha, S.K., Tvorogov, D., Anisimov, A., Leppänen, V.M., Holopainen, T., Kivelä R., Ortega, S., Kärpanen, T., Alitalo, K., CCBE1 enhances lymphangiogenesis via ADAMTS3-mediated VEGF-C activation. Circulation 129 (2014), 1962–1971.
Brouillard, P., Dupont, L., Helaers, R., Coulie, R., Tiller, G.E., Peeden, J., Colige, A., Vikkula, M., Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3. Hum. Mol. Genet.(21), 2017, 4095–4104.
Goertsches, R., Comabella, M., Navarro, A., Perkal, H., Montalban, X., Genetic association between polymorphisms in the ADAMTS14 gene and multiple sclerosis. J. Neuroimmunol. 164 (2005), 140–147.
Rodriguez-Lopez, J., Pombo-Suarez, M., Loughlin, J., Tsezou, A., Blanco, F.J., Meulenbelt, I., Slagboom, P.E., Valdes, A.M., Spector, T.D., Gomez-Reino, J.J., Gonzalez, A., Association of a nsSNP in ADAMTS14 to some osteoarthritis phenotypes. Osteoarthr. Cartil. 17 (2009), 321–327.
Dubail, J., Kesteloot, F., Deroanne, C., Motte, P., Lambert, V., Rakic, J.M., Lapiere, C., Nusgens, B., Colige, A., ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity. Cell. Mol. Life Sci. 67 (2010), 4213–4232.
Hofer, T.P., Frankenberger, M., Mages, J., Lang, R., Meyer, P., Hoffmann, R., Colige, A., Ziegler-Heitbrock, L., Tissue-specific induction of ADAMTS2 in monocytes and macrophages by glucocorticoids. J. Mol. Med. 86 (2008), 323–332.
Arning, A., Hiersche, M., Witten, A., Kurlemann, G., Kurnik, K., Manner, D., Stoll, M., Nowak-Gottl, U., A genome-wide association study identifies a gene network of ADAMTS genes in the predisposition to pediatric stroke. Blood 120 (2012), 5231–5236.
Lee, C.W., Hwang, I., Park, C.S., Lee, H., Park, D.W., Kang, S.J., Lee, S.W., Kim, Y.H., Park, S.W., Park, S.J., Expression of ADAMTS-2, -3, -13, and -14 in culprit coronary lesions in patients with acute myocardial infarction or stable angina. J. Thromb. Thrombolysis 33 (2012), 362–370.
Shigeoka, T., Kawaichi, M., Ishida, Y., Suppression of nonsense-mediated mRNA decay permits unbiased gene trapping in mouse embryonic stem cells. Nucleic Acids Res., 33, 2005, e20.
Le Goff, C., Morice-Picard, F., Dagoneau, N., Wang, L.W., Perrot, C., Crow, Y.J., Bauer, F., Flori, E., Prost-Squarcioni, C., Krakow, D., Ge, G., Greenspan, D.S., Bonnet, D., Le Merrer, M., Munnich, A., Apte, S.S., Cormier-Daire, V., ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-beta bioavailability regulation. Nat. Genet. 40 (2008), 1119–1123.
Uitto, J., Has, C., Vahidnezhad, H., Youssefian, L., Bruckner-Tuderman, L., Molecular pathology of the basement membrane zone in heritable blistering diseases: the paradigm of epidermolysis bullosa. Matrix Biol. 57–58 (2017), 76–85.
Bekhouche, M., Colige, A., The procollagen N-proteinases ADAMTS2, 3 and 14 in pathophysiology. Matrix Biol. 44–46 (2015), 46–53.
Prox, J., Arnold, P., Becker-Pauly, C., Meprin α and meprin β: procollagen proteinases in health and disease. Matrix Biol. 44–46 (May–Jul 2015), 7–13.
Di Meglio, P., Villanova, F., Nestle, F.O., Psoriasis. CSH Perspect. Med. 8 (2014), 1–4.
van der Fits, L., Mourits, S., Voerman, J.S., Kant, M., Boon, L., Laman, J.D., Cornelissen, F., Mus, A.M., Florencia, E., Prens, E.P., Lubberts, E., Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182 (2009), 5836–5845.
Cai, Y., Shen, X., Ding, C., Qi, C., Li, K., Li, X., Jala, V.R., Zhang, H.G., Wang, T., Zheng, J., Yan, J., Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity 35 (2011), 596–610.
Kaul, A., Gordon, C., Crow, M.K., Touma, Z., Urowitz, M.B., van Vollenhoven, R., Ruiz-Irastorza, G., Hughes, G., Systemic lupus erythematosus. Nat. Rev. Dis. Primers, 2, 2016 (n° 16039).
Levin, J., Fallon Friedlander, S., Del Rosso, J.Q., Atopic dermatitis and the stratum corneum: part 3: the immune system in atopic dermatitis. J. Clin. Aesthet. Dermatol. 6 (2013), 37–44.
Somers, E.C., Marder, W., Cagnoli, P., Lewis, E.E., DeGuire, P., Gordon, C., Helmick, C.G., Wang, L., Wing, J.J., Dhar, J.P., Leisen, J., Shaltis, D., McCune, W.J., Population-based incidence and prevalence of systemic lupus erythematosus: the Michigan lupus epidemiology and surveillance program. Arthritis Rheumatol. 66 (2014), 369–378.
Bieber, T., Atopic dermatitis. N. Engl. J. Med. 358 (2008), 1483–1494.
Tokura, Y., Extrinsic and intrinsic types of atopic dermatitis. J. Dermatol. Sci. 58 (2010), 1–7.
Eyerich, K., Novak, N., Immunology of atopic eczema: overcoming the Th1/Th2 paradigm. Allergy 68 (2013), 974–982.
Bekhouche, M., Leduc, C., Dupont, L., Janssen, L., Delolme, F., Vadon-Le Goff, S., Smargiasso, N., Baiwir, D., Mazzucchelli, G., Zanella-Cleon, I., Dubail, J., De Pauw, E., Nusgens, B., Hulmes, D.J., Moali, C., Colige, A., Determination of the substrate repertoire of ADAMTS2, 3, and 14 significantly broadens their functions and identifies extracellular matrix organization and TGF-β signaling as primary targets. FASEB J. 30 (2016), 1741–1756.
Li, N., Hua, J., Interactions between mesenchymal stem cells and the immune system. Cell. Mol. Life Sci. 74 (2017), 2345–2360.
Komai, T., Inoue, M., Morita, K., Okamura, T., Yamamoto, K., Revisiting the regulatory roles of the TGF-β family of cytokines. Autoimmun. Rev. 15 (2016), 917–922.
Myllyharju, J., Kivirikko, K.I., Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet. 20 (2004), 33–43.