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

Matrix Biol. 2018 Sep:70:140-157. doi: 10.1016/j.matbio.2018.04.002. Epub 2018 Apr 9.

Abstract

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.

Keywords: ADAMTS; Collagen; Dermatitis; Immunity; Skin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS Proteins / deficiency
  • ADAMTS Proteins / genetics
  • ADAMTS Proteins / immunology*
  • Animals
  • Cell Differentiation
  • Cell Movement
  • Dermatitis, Atopic / genetics
  • Dermatitis, Atopic / immunology*
  • Dermatitis, Atopic / pathology
  • Dermis / immunology*
  • Dermis / pathology
  • Epidermis / immunology*
  • Epidermis / pathology
  • Extracellular Matrix / immunology
  • Extracellular Matrix / pathology
  • Female
  • Gene Expression Regulation
  • Immunity, Innate
  • Isoenzymes / deficiency
  • Isoenzymes / genetics
  • Isoenzymes / immunology
  • Male
  • Mice
  • Mice, Knockout
  • Procollagen / genetics
  • Procollagen / immunology*
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / immunology

Substances

  • Isoenzymes
  • Procollagen
  • Transforming Growth Factor beta
  • ADAMTS Proteins
  • Adamts14 protein, mouse
  • Adamts2 protein, mouse