In this study, a total 515 DEGs between lesional and non-lesional skin samples were screened, including 286 up- and 229 downregulated genes. The enriched functions for the up- and downregulated genes were primarily in the BP category.
Being an allergen-induced gene in experimental allergic responses, small proline-rich protein 2 (SPRR2) may be associated with allergic inflammation . SPR1 and SPR2 in the epidermis, as well as SPR3 in cultured keratinocytes, may be epidermal cell envelope (CE) components [23, 24]. Some members of the SPRR-family are overexpressed during ageing, thereby reducing the skin’s barrier function against hostile attacks from the environment . We found that SPRR2C was among the top 30 upregulated DEGs in the blue module and was significantly correlated (correlation coefficient = 0.94) with AE, indicating that the expression levels of SPRR2C may be related to AE.
As a peoptide antibiotic, human b-defensin-2 (hBD-2, also known as DEFB4A) can protect human skin with psoriasis from infection by abnormal expression in response to invasion of microorganisms . Overexpression of hBD-2, which can be induced by Staphylococcus aureus, can cause persistent eczematous skin lesions in patients with AE . Expression of hBD-2 can be induced by injury, inflammatory stimuli, and bacteria on the skin of AE patients . In addition, serum hBD-2 levels may be enhanced by oncostatin M and interleukin-22 (IL-22) through transcription 3 (STAT3) in keratinocytes, and this may also function as a biomarker of skin inflammation . Additionally, the correlation between high DEFB4 expression and psoriasis risk indicates that hBD2 may play a role in the skin’s inflammatory response . We also found that upregulated DEFB4A was among the top 30 DEGs in the blue module significantly correlated (correlation coefficient = 0.94) with AE, indicating that DEFB4A might play a role in AE.
Abnormal circadian clockwork often induces bipolar disorders and depression in patients. As a circadian gene, CRY2 is involved in regulating the evening oscillator . CRY2 exists in the epidermis, plays an important role in maintaining the epidermal clock, and cannot be replaced by external light . The variable expression of KRT15andKRT19 in oral squamous cell carcinoma (OSCC) and squamous intraepithelial neoplasm (SIN) results in their divergent biological behaviors and roles in pathogenesis, indicating that they may be used as markers to classify OSCC and SIN . KRT19 may also function as a specific epithelial marker . Expression of KRT19 in the skin may be an additional characterization of skin stem cells under pathological and normal conditions . In our study, we found that downregulated CRY2 and KRT19 were among the top 30 DEGs in the brown module significantly correlated (correlation coefficient = 0.97) with AE. These might indicate that the expression levels of CRY2 and KRT19 are related to AE.
Downregulation of WIF1 is implicated in melasma development by upregulating the canonical or noncanonical Wnt signaling pathway . Although Wnt signaling regulates skin pigmentation, WIF1 is expressed not only in melanocytes, but also in keratinocytes [37, 38] and fibroblasts . WIF1 expression is upregulated in interfollicular keratinocyte stem cells (KSCs), which is of great interest given the increased levels of Wnt signaling in psoriasis, wound healing, and basal cell carcinomas [40, 41]. WIF1 can function as a marker of interfollicular KSCs and can inhibit cell cycle progression in human keratinocytes, even under the activation of Wnt signals (Wnt3A) . We also found that downregulated WIF1 was among the top 30 DEGs in the brown module significantly correlated (correlation coefficient = 0.97) with AE. This indicated that WIF1 might be associated with AE.
In this study, KEGG pathway analysis revealed that the upregulated genes in the blue module were primarily involved in the cytokine-cytokine receptor interaction. Cytokine-cytokine receptor interaction is associated with the progression of skin-related diseases by regulating the proliferation of skin-derived precursors (SKPs) and SKP differentiation . In addition, cytokine-cytokine receptor interaction has previously been demonstrated to play an important role in the progression of AE . Thus, we inferred that cytokine-cytokine receptor interaction might be closely correlated with the AE progression.
In the present study, a weighted correlation network analysis was utilized to identify key genes involved in AE, providing a basis for further study of AE. However, relevant experiments should be conducted to verify the numerous candidate genes and signaling pathways identified in this study. In addition, in depth research is required to elucidate the specific mechanisms of action in AE.
In conclusion, we performed a comprehensive bioinformatics analysis of genes which may be involved in AE. SPRR2C, DEFB4A, WIF1, CRY2, KRT19, and cytokine-cytokine receptor interaction might play a role in AE.