Activation of Molecular Signatures for Antimicrobial and Innate Defense Responses in Skin with Transglutaminase 1 Deficiency

<div><p>Mutations of the <i>transglutaminase 1</i> gene (<i>TGM1</i>) are a major cause of autosomal recessive congenital ichthyoses (ARCIs) that are associated with defects in skin barrier structure and function. However, the molecular processes induced by the transglutaminase 1 deficiency are not fully understood. The aim of the present study was to uncover those processes by analysis of cutaneous molecular signatures. Gene expression profiles of wild-type and <i>Tgm1</i><sup>–/–</sup>epidermis were assessed using microarrays. Gene ontology analysis of the data showed that genes for innate defense responses were up-regulated in <i>Tgm1</i><sup>–/–</sup>epidermis. Based on that result, the induction of <i>Il1b</i> and antimicrobial peptide genes, <i>S100a8</i>, <i>S100a9</i>, <i>Defb14</i>, <i>Camp</i>, <i>Slpi</i>, <i>Lcn2</i>, <i>Ccl20</i> and <i>Wfdc12</i>, was confirmed by quantitative real-time PCR. A protein array revealed that levels of IL-1β, G-CSF, GM-CSF, CXCL1, CXCL2, CXCL9 and CCL2 were increased in <i>Tgm1</i><sup>–/–</sup>skin. Epidermal growth factor receptor (EGFR) ligand genes, <i>Hbegf</i>, <i>Areg</i> and <i>Ereg</i>, were activated in <i>Tgm1</i><sup>–/–</sup>epidermis. Furthermore, the antimicrobial activity of an epidermal extract from <i>Tgm1</i><sup>–/–</sup>mice was significantly increased against both <i>Escherichia coli</i> and <i>Staphylococcus aureus</i>. In the epidermis of ichthyosiform skins from patients with <i>TGM1</i> mutations, S100A8/9 was strongly positive. The expression of those antimicrobial and defense response genes was also increased in the lesional skin of an ARCI patient with <i>TGM1</i> mutations. These results suggest that the up-regulation of molecular signatures for antimicrobial and innate defense responses is characteristic of skin with a transglutaminase 1 deficiency, and this autonomous process might be induced to reinforce the defective barrier function of the skin.</p></div>