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

Mutations of the transglutaminase 1 gene (TGM1) 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 Tgm1–/–epidermis were assessed using microarrays. Gene ontology analysis of the data showed that genes for innate defense responses were up-regulated in Tgm1–/–epidermis. Based on that result, the induction of Il1b and antimicrobial peptide genes, S100a8, S100a9, Defb14, Camp, Slpi, Lcn2, Ccl20 and Wfdc12, 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 Tgm1–/–skin. Epidermal growth factor receptor (EGFR) ligand genes, Hbegf, Areg and Ereg, were activated in Tgm1–/–epidermis. Furthermore, the antimicrobial activity of an epidermal extract from Tgm1–/–mice was significantly increased against both Escherichia coli and Staphylococcus aureus. In the epidermis of ichthyosiform skins from patients with TGM1 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 TGM1 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.

转谷氨酰胺酶1基因（transglutaminase 1 gene, TGM1）突变是引发常染色体隐性先天性鱼鳞病（autosomal recessive congenital ichthyoses, ARCI）的主要病因，此类疾病伴随皮肤屏障结构与功能缺陷。然而，转谷氨酰胺酶1缺乏所介导的分子调控过程尚未完全阐明。本研究旨在通过分析皮肤分子特征，揭示此类调控过程。研究人员利用基因微阵列检测了野生型与Tgm1基因敲除（Tgm1–/–）小鼠表皮的基因表达谱。对数据进行基因本体（Gene Ontology, GO）富集分析后发现，固有免疫防御相关基因在Tgm1–/–表皮中呈现上调表达。基于该结果，研究人员通过实时荧光定量PCR验证了Il1b及抗菌肽基因S100a8、S100a9、Defb14、Camp、Slpi、Lcn2、Ccl20与Wfdc12的诱导表达情况。蛋白质芯片检测结果显示，Tgm1–/–皮肤中IL-1β、粒细胞集落刺激因子（G-CSF）、粒细胞-巨噬细胞集落刺激因子（GM-CSF）、CXCL1、CXCL2、CXCL9及CCL2的蛋白水平显著升高。表皮生长因子受体（EGFR）配体基因Hbegf、Areg与Ereg在Tgm1–/–表皮中被激活。此外，Tgm1–/–小鼠表皮提取物对大肠杆菌（Escherichia coli）与金黄色葡萄球菌（Staphylococcus aureus）的抗菌活性均显著增强。在携带TGM1突变的鱼鳞病样皮损患者表皮中，S100A8/9呈强阳性表达。在一例携带TGM1突变的常染色体隐性先天性鱼鳞病患者的皮损组织中，上述抗菌及防御相关基因的表达同样出现上调。上述结果表明，抗菌与固有免疫防御相关分子特征的上调是转谷氨酰胺酶1缺乏型皮肤的标志性特征，该自主调控过程或可通过强化存在缺陷的皮肤屏障功能发挥代偿作用。