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Bacterially Delivered miRNA-Mediated Toll-like Receptor 8 Gene Silencing for Combined Therapy in a Murine Model of Atopic Dermatitis: Therapeutic Effect of miRTLR8 in AD

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 pat...

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Autores principales: Yoon, Wonsuck, Kim, Eun-Jae, Park, Yongsung, Kim, Seunghyun, Park, Yong-Keun, Yoo, Young
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401271/
https://www.ncbi.nlm.nih.gov/pubmed/34442794
http://dx.doi.org/10.3390/microorganisms9081715
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author Yoon, Wonsuck
Kim, Eun-Jae
Park, Yongsung
Kim, Seunghyun
Park, Yong-Keun
Yoo, Young
author_facet Yoon, Wonsuck
Kim, Eun-Jae
Park, Yongsung
Kim, Seunghyun
Park, Yong-Keun
Yoo, Young
author_sort Yoon, Wonsuck
collection PubMed
description 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.
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spelling pubmed-84012712021-08-29 Bacterially Delivered miRNA-Mediated Toll-like Receptor 8 Gene Silencing for Combined Therapy in a Murine Model of Atopic Dermatitis: Therapeutic Effect of miRTLR8 in AD Yoon, Wonsuck Kim, Eun-Jae Park, Yongsung Kim, Seunghyun Park, Yong-Keun Yoo, Young Microorganisms Article 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. MDPI 2021-08-12 /pmc/articles/PMC8401271/ /pubmed/34442794 http://dx.doi.org/10.3390/microorganisms9081715 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yoon, Wonsuck
Kim, Eun-Jae
Park, Yongsung
Kim, Seunghyun
Park, Yong-Keun
Yoo, Young
Bacterially Delivered miRNA-Mediated Toll-like Receptor 8 Gene Silencing for Combined Therapy in a Murine Model of Atopic Dermatitis: Therapeutic Effect of miRTLR8 in AD
title Bacterially Delivered miRNA-Mediated Toll-like Receptor 8 Gene Silencing for Combined Therapy in a Murine Model of Atopic Dermatitis: Therapeutic Effect of miRTLR8 in AD
title_full Bacterially Delivered miRNA-Mediated Toll-like Receptor 8 Gene Silencing for Combined Therapy in a Murine Model of Atopic Dermatitis: Therapeutic Effect of miRTLR8 in AD
title_fullStr Bacterially Delivered miRNA-Mediated Toll-like Receptor 8 Gene Silencing for Combined Therapy in a Murine Model of Atopic Dermatitis: Therapeutic Effect of miRTLR8 in AD
title_full_unstemmed Bacterially Delivered miRNA-Mediated Toll-like Receptor 8 Gene Silencing for Combined Therapy in a Murine Model of Atopic Dermatitis: Therapeutic Effect of miRTLR8 in AD
title_short Bacterially Delivered miRNA-Mediated Toll-like Receptor 8 Gene Silencing for Combined Therapy in a Murine Model of Atopic Dermatitis: Therapeutic Effect of miRTLR8 in AD
title_sort bacterially delivered mirna-mediated toll-like receptor 8 gene silencing for combined therapy in a murine model of atopic dermatitis: therapeutic effect of mirtlr8 in ad
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401271/
https://www.ncbi.nlm.nih.gov/pubmed/34442794
http://dx.doi.org/10.3390/microorganisms9081715
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