Homeostatic Function of Dermokine in the Skin Barrier and Inflammation.

Dermokine is a chiefly skin-specific secreted glycoprotein localized in the upper epidermis, and its family consists of three splice variants in mice and five in humans. To investigate the pathophysiological impact of dermokine, we generated mice deficient for two (ßγ) or all dermokine isoforms (αßγ). Both variants, especially dermokine αßγ-deficient mice exhibited scale and wrinkle formation resembling ichthyosis accompanied by transepidermal water imbalance at the neonatal stage. Several dermokine αßγ-deficient mice died by postnatal day 21 when reared under low humidity. Moreover, the cornified envelope was vulnerable, and skin barrier lipid ceramides were reduced in the epidermis of dermokine αßγ-deficient mice. cDNA microarray and quantitative reverse transcriptase-PCR assays of the epidermis revealed the upregulation of small proline-rich protein and late cornified envelope family members, as well as antimicrobial peptides in the dermokine αßγ-deficient mice. These barrier gene signatures were similar to that seen in psoriasis, whereas recent studies demonstrated that congenital ichthyosis has gene profiles resembling psoriasis. In line with these findings, adult dermokine αßγ-deficient mice exhibited aggravated phenotypes in psoriasis-like dermatitis models but not in allergic dermatitis models. Dermokine may play a regulatory role in inflammatory dyskeratotic diseases, such as congenital ichthyosis and psoriasis, in the crosstalk between barrier dysfunction and inflammation.

Fetal inhibition of inflammation improves disease phenotypes in harlequin ichthyosis.

Harlequin ichthyosis (HI) is a severe skin disease which leads to neonatal death in ∼50% of cases. It is the result of mutations in ABCA12, a protein that transports lipids required to establish the protective skin barrier needed after birth. To better understand the life-threatening newborn HI phenotype, we analysed the developing epidermis for consequences of lipid dysregulation in mouse models. We observed a pro-inflammatory signature which was characterized by chemokine upregulation in embryonic skin which is distinct from that seen in other types of ichthyosis. Inflammation also persisted in grafted HI skin. To examine the contribution of inflammation to disease development, we overexpressed interleukin-37b to globally suppress fetal inflammation, observing considerable improvements in keratinocyte differentiation. These studies highlight inflammation as an unexpected contributor to HI disease development in utero, and suggest that inhibiting inflammation may reduce disease severity.

Abnormal lamellar granules in harlequin ichthyosis.

Lamellar granules are specialized lipid-rich organelles present in epidermal granular cells. They fuse with the apical cell surface and discharge their contents into the intercellular space forming lamellar sheets. It was previously shown by electron microscopy that lamellar granules in biopsies of infants affected with harlequin ichthyosis are either absent or abnormal and no intercellular lamellae could be detected. A monoclonal antibody (AE17) directed against a protein component of lamellar granules was used for immunoblotting and immunohistochemical studies as an indication of both the presence and function of lamellar granules. Epidermal extracts from all harlequin and normal specimens tested showed an immunoreactive protein of 25-28 kD. Immunohistochemical staining of normal skin using AE17 showed apical cytoplasmic staining in the granular layer and intercellular staining between the granular and stratum corneum cells. Harlequin samples showed variable degrees of staining ranging from little to heavy apical cytoplasmic staining of granular cells. No intercellular staining was detected. The immunohistochemical staining pattern correlated with the electron microscopic localization of abnormal vesicles and the absence of intercellular lamellae in the affected samples. We conclude that the vesicles represent lamellar granules that contain the AE17 antigen but are structurally abnormal and defective in their ability to discharge both their lipid and protein contents into the intercellular space. We suggest that this defect in the lamellar granules represents the underlying basis for stratum corneum cell retention and subsequent accumulation of scale in harlequin ichthyosis.