Abstract
In atopic dermatitis (AD), skin inflammation is caused by complex interactions between genetic disposition and aberrant innate/adaptive immune responses. Toll-like receptors (TLRs) are key molecules in the innate/adaptive immune response as they recognize various molecular motifs associated with pathogens. Among them, TLR8 is implicated in eczematous skin reactions. We investigated the combined therapeutic effects of TLR8 gene silencing by the bacterial delivery of miRNA. We used Salmonella as a vector to deliver TLR8 miRNA. The recombinant strain of Salmonella enterica subsp. enterica serovar Typhimurium (ST) expressing TLR8 miRNA (ST-miRTLR8) was prepared for knockdown of TLR8. After oral administration of ST-miRTLR8 into mice, we observed the cytokine levels, skin pathology and scratching behaviors in an AD-like mouse model. TLR8 down-regulation decreased macrophage-derived chemokine concentrations in activated human mast cells. Serum IgE and interleukin-4 production were suppressed whereas IFN-γ was induced after oral administration of ST-miRTLR8. Scratching behaviors and skin inflammation were also improved. In addition, attenuated S. typhimurium safely accumulated in mouse macrophages and showed adjuvant effects. This study shows that the recombinant miRNA that expresses the TLR8 miRNA has therapeutic effects by suppressing Th2 inflammation. TLR gene modulation using miRNA via Salmonella vectors will thus have a double-protective effect in the treatment of AD.
Highlights
We examined TLR8 expression in the peripheral blood mononuclear cells (PBMCs) of patients with atopic dermatitis (AD)
Immunoblot analysis showed that TLR8 protein expression was significantly higher in the PBMC cells of patients with AD than in those of normal controls (Figure 1A,B)
TLR8-specific miRNA may serve as a therapeutic candidate for AD
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Atopic dermatitis (AD) is a chronic condition that usually begins in childhood but often persists into adulthood [1]. The exact etiology is unclear, it is clear that the complex interplay between barrier dysfunction, inflammation and pruritus is important for development, progression and chronicity. Skin inflammation is related to abnormalities of filaggrin, intercellular lipids, tight junctions, thymic interstitial lymphoetin and tolllike receptors (TLRs) [2,3]. Skin inflammation comprises complex interactions between genetic predisposition, imbalanced systemic and/or local immune responses and skin barrier dysfunction [4]. In AD, variations in the innate immune responses can prime a deviation of the adaptive immune response, skewing to dominance of Th2 cytokines such as interleukins (ILs) 4, 5 and 10 [5]
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