Semaphorin 7a Regulates the Expression of IL-4 and IL-33 in a Cell Model of Atopic Dermatitis and Is Associated With Disease Severity

Abstract

Neuroimmune interaction is crucial to inducing pruritic sensations in atopic dermatitis (AD). In this study, we examine the neuroimmune pathways involved in children with AD. HumanMethylation450 BeadChip and GeneChip Human Transcriptome Array 2.0 from 24 children with ad and 24 healthy controls were cross-referenced with gene expression data from GSE116486. SEMA7A, which encodes for semaphorin 7a and is associated with neuron development and immune response and was identified on pathway analysis as a crucial gene in children with ad. In addition, we found that SEMA7A cytosine-phosphate-guanine sites (CpG sites) cg13557411 and cg17917837 were hypomethylated, and mRNA expression of SEMA7A was higher in children with ad. Vectors containing SEMA7A were then transfected into Jurkat T cells, which increased the protein excretion of interleukin 4 (IL-4) and the mRNA expression of interleukin 1 receptor-like 1 (IL1RL1, receptor for the cytokine IL-33). Furthermore, stimulation of HaCaT keratinocytes with SEMA7A protein resulted in increased mRNA expression of the genes interleukin 33 (IL33) and IL1RL1, but suppressed mRNA expression of the tight junction protein ZO-1(TJP1). In conclusion, in this study, we found that SEMA7A is overexpressed in patients with AD and is a central gene on pathway analysis. Results of our study suggest that overexpression of SEMA7A is associated with increased expression of IL4, IL33 and its receptor IL1RL1, which are associated with pruritic sensation in AD. SEMA7A also appears to suppress the expression of TJP1 in keratinocytes, thereby possibly increasing the permeability of the skin barrier. SEMA7A may be an alternative therapeutic target in AD, especially for neuroimmune-related pruritis.