Rapamycin Alleviates 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Aggravated Dermatitis in Mice with Imiquimod-Induced Psoriasis-Like Dermatitis by Inducing Autophagy
Recently, the mTOR signaling has emerged as an important player in the pathogenesis of psoriasis. We previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced psoriatic skin inflammation was related to the inhibition of autophagy in keratinocytes. However, the effects and detailed mol...
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| description | Recently, the mTOR signaling has emerged as an important player in the pathogenesis of psoriasis. We previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced psoriatic skin inflammation was related to the inhibition of autophagy in keratinocytes. However, the effects and detailed molecular mechanisms of the mTOR inhibitor rapamycin and TCDD on psoriasis in vivo remain to be elucidated. In this study, we aimed to evaluate the effects of rapamycin and TCDD on skin lesions in imiquimod (IMQ)-induced psoriasis using a mouse model. TCDD aggravated skin inflammation in an IMQ-induced psoriatic mouse model. Furthermore, TCDD increased the expression of aryl hydrocarbon receptor (AHR), CYP1A1, proinflammatory cytokines, oxidative stress markers (NADPH oxidase (Nox) 2, Nox4), and phosphorylated P65NF-ĸB, whereas the expression of autophagy-related factors and the antioxidant marker nuclear factor-erythroid 2-related factor 2 (NRF2) decreased. Rapamycin reduced the aggravated skin inflammation induced by TCDD and restored TCDD-induced autophagy suppression and the increase of AHR expression, oxidative stress, and inflammatory response in the skin lesions of a psoriatic mouse model. In conclusion, we demonstrated that rapamycin alleviates TCDD-induced aggravated dermatitis in mice with imiquimod-induced psoriasis-like dermatitis through AHR and autophagy modulation. |
| doi_str_mv | 10.3390/ijms22083968 |
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We previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced psoriatic skin inflammation was related to the inhibition of autophagy in keratinocytes. However, the effects and detailed molecular mechanisms of the mTOR inhibitor rapamycin and TCDD on psoriasis in vivo remain to be elucidated. In this study, we aimed to evaluate the effects of rapamycin and TCDD on skin lesions in imiquimod (IMQ)-induced psoriasis using a mouse model. TCDD aggravated skin inflammation in an IMQ-induced psoriatic mouse model. Furthermore, TCDD increased the expression of aryl hydrocarbon receptor (AHR), CYP1A1, proinflammatory cytokines, oxidative stress markers (NADPH oxidase (Nox) 2, Nox4), and phosphorylated P65NF-ĸB, whereas the expression of autophagy-related factors and the antioxidant marker nuclear factor-erythroid 2-related factor 2 (NRF2) decreased. Rapamycin reduced the aggravated skin inflammation induced by TCDD and restored TCDD-induced autophagy suppression and the increase of AHR expression, oxidative stress, and inflammatory response in the skin lesions of a psoriatic mouse model. In conclusion, we demonstrated that rapamycin alleviates TCDD-induced aggravated dermatitis in mice with imiquimod-induced psoriasis-like dermatitis through AHR and autophagy modulation.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms22083968</identifier><identifier>PMID: 33921372</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Animals ; Antioxidants ; Antiviral drugs ; Autophagy ; Autophagy - drug effects ; Autophagy - genetics ; Cell Differentiation - drug effects ; Cells, Cultured ; Cytochrome P-450 CYP1A1 - genetics ; Cytochrome P450 ; Cytokines ; Dermatitis ; Dermatitis - drug therapy ; Dermatitis - etiology ; Dermatitis - pathology ; Dioxins ; Disease ; Gene Expression Regulation - drug effects ; Humans ; Hyperplasia ; Imiquimod ; Imiquimod - toxicity ; In vivo methods and tests ; Inflammation ; Inflammation - chemically induced ; Inflammation - drug therapy ; Inflammation - genetics ; Inflammation - pathology ; Inflammatory response ; Keratinocytes ; Keratinocytes - drug effects ; Lesions ; Markers ; Mice ; Molecular modelling ; NAD(P)H oxidase ; NADPH Oxidase 4 - genetics ; NF-E2-Related Factor 2 - genetics ; NOX4 protein ; Oxidative stress ; Pathogenesis ; Phagocytosis ; Polychlorinated Dibenzodioxins - toxicity ; Psoriasis ; Psoriasis - chemically induced ; Psoriasis - drug therapy ; Psoriasis - genetics ; Psoriasis - pathology ; Rapamycin ; Receptors, Aryl Hydrocarbon - genetics ; Sirolimus - pharmacology ; Skin ; Skin diseases ; Skin lesions ; Spleen ; TCDD ; TOR protein</subject><ispartof>International journal of molecular sciences, 2021-04, Vol.22 (8), p.3968</ispartof><rights>2021 by the authors. 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/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-18fc5c247c58a262339e62096528712e3b80b958fee5f3624d38b44a304e5e543</citedby><cites>FETCH-LOGICAL-c412t-18fc5c247c58a262339e62096528712e3b80b958fee5f3624d38b44a304e5e543</cites><orcidid>0000-0002-2795-0140 ; 0000-0002-1523-6951 ; 0000-0001-6532-2244 ; 0000-0001-7519-8910 ; 0000-0001-5846-0008</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069848/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069848/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33921372$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Hye Ran</creatorcontrib><creatorcontrib>Kim, Jin Cheol</creatorcontrib><creatorcontrib>Kang, Seok Young</creatorcontrib><creatorcontrib>Kim, Hye One</creatorcontrib><creatorcontrib>Park, Chun Wook</creatorcontrib><creatorcontrib>Chung, Bo Young</creatorcontrib><title>Rapamycin Alleviates 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Aggravated Dermatitis in Mice with Imiquimod-Induced Psoriasis-Like Dermatitis by Inducing Autophagy</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Recently, the mTOR signaling has emerged as an important player in the pathogenesis of psoriasis. We previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced psoriatic skin inflammation was related to the inhibition of autophagy in keratinocytes. However, the effects and detailed molecular mechanisms of the mTOR inhibitor rapamycin and TCDD on psoriasis in vivo remain to be elucidated. In this study, we aimed to evaluate the effects of rapamycin and TCDD on skin lesions in imiquimod (IMQ)-induced psoriasis using a mouse model. TCDD aggravated skin inflammation in an IMQ-induced psoriatic mouse model. Furthermore, TCDD increased the expression of aryl hydrocarbon receptor (AHR), CYP1A1, proinflammatory cytokines, oxidative stress markers (NADPH oxidase (Nox) 2, Nox4), and phosphorylated P65NF-ĸB, whereas the expression of autophagy-related factors and the antioxidant marker nuclear factor-erythroid 2-related factor 2 (NRF2) decreased. Rapamycin reduced the aggravated skin inflammation induced by TCDD and restored TCDD-induced autophagy suppression and the increase of AHR expression, oxidative stress, and inflammatory response in the skin lesions of a psoriatic mouse model. In conclusion, we demonstrated that rapamycin alleviates TCDD-induced aggravated dermatitis in mice with imiquimod-induced psoriasis-like dermatitis through AHR and autophagy modulation.</description><subject>Animals</subject><subject>Antioxidants</subject><subject>Antiviral drugs</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Autophagy - genetics</subject><subject>Cell Differentiation - drug effects</subject><subject>Cells, Cultured</subject><subject>Cytochrome P-450 CYP1A1 - genetics</subject><subject>Cytochrome P450</subject><subject>Cytokines</subject><subject>Dermatitis</subject><subject>Dermatitis - drug therapy</subject><subject>Dermatitis - etiology</subject><subject>Dermatitis - pathology</subject><subject>Dioxins</subject><subject>Disease</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Humans</subject><subject>Hyperplasia</subject><subject>Imiquimod</subject><subject>Imiquimod - toxicity</subject><subject>In vivo methods and tests</subject><subject>Inflammation</subject><subject>Inflammation - chemically induced</subject><subject>Inflammation - drug therapy</subject><subject>Inflammation - genetics</subject><subject>Inflammation - pathology</subject><subject>Inflammatory response</subject><subject>Keratinocytes</subject><subject>Keratinocytes - drug effects</subject><subject>Lesions</subject><subject>Markers</subject><subject>Mice</subject><subject>Molecular modelling</subject><subject>NAD(P)H oxidase</subject><subject>NADPH Oxidase 4 - genetics</subject><subject>NF-E2-Related Factor 2 - genetics</subject><subject>NOX4 protein</subject><subject>Oxidative stress</subject><subject>Pathogenesis</subject><subject>Phagocytosis</subject><subject>Polychlorinated Dibenzodioxins - toxicity</subject><subject>Psoriasis</subject><subject>Psoriasis - chemically induced</subject><subject>Psoriasis - drug therapy</subject><subject>Psoriasis - genetics</subject><subject>Psoriasis - pathology</subject><subject>Rapamycin</subject><subject>Receptors, Aryl Hydrocarbon - genetics</subject><subject>Sirolimus - pharmacology</subject><subject>Skin</subject><subject>Skin diseases</subject><subject>Skin lesions</subject><subject>Spleen</subject><subject>TCDD</subject><subject>TOR protein</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkUuP00AQhC0EYpeFG2dkicseYhj3PDy-IEXLK1IQCC1nazxuOx1sT3bGDoT_w_9kYJcocOqW-qtSlypJnubsBecle0nbIQAwzUul7yXnuQDIGFPF_ZP9LHkUwpYx4CDLh8lZFELOCzhPfn42OzMcLI3psu9xT2bCkMKCL4qFzq5x8sZueuddQzWOP1y2yxpy32nMVmMzW2zSZdd5s4-yJn2NfjATTRTS6PeBLKbfaNqkq4FuZhpccxR9Cs6TCRSyNX3FU2F9SP9ANHbpcp7cbmO6w-PkQWv6gE_u5kXy5e2b66v32frju9XVcp1ZkcOU5bq10oIorNQGFMSYqICVSoIuckBea1aXUreIsuUKRMN1LYThTKBEKfhF8urWdzfXAzYWx5i_r3aeBuMPlTNU_XsZaVN1bl9ppkotdDS4vDPw7mbGMFUDBYt9b0Z0c6hAxqYUA5lH9Pl_6NbNfozxIiW0EirXZaQWt5T1LgSP7fGZnFW_-69O-4_4s9MAR_hv4fwXdWit2A</recordid><startdate>20210412</startdate><enddate>20210412</enddate><creator>Kim, Hye Ran</creator><creator>Kim, Jin Cheol</creator><creator>Kang, Seok Young</creator><creator>Kim, Hye One</creator><creator>Park, Chun Wook</creator><creator>Chung, Bo Young</creator><general>MDPI AG</general><general>MDPI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-2795-0140</orcidid><orcidid>https://orcid.org/0000-0002-1523-6951</orcidid><orcidid>https://orcid.org/0000-0001-6532-2244</orcidid><orcidid>https://orcid.org/0000-0001-7519-8910</orcidid><orcidid>https://orcid.org/0000-0001-5846-0008</orcidid></search><sort><creationdate>20210412</creationdate><title>Rapamycin Alleviates 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Aggravated Dermatitis in Mice with Imiquimod-Induced Psoriasis-Like Dermatitis by Inducing Autophagy</title><author>Kim, Hye Ran ; Kim, Jin Cheol ; Kang, Seok Young ; Kim, Hye One ; Park, Chun Wook ; Chung, Bo Young</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-18fc5c247c58a262339e62096528712e3b80b958fee5f3624d38b44a304e5e543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Antioxidants</topic><topic>Antiviral drugs</topic><topic>Autophagy</topic><topic>Autophagy - drug effects</topic><topic>Autophagy - genetics</topic><topic>Cell Differentiation - drug effects</topic><topic>Cells, Cultured</topic><topic>Cytochrome P-450 CYP1A1 - genetics</topic><topic>Cytochrome P450</topic><topic>Cytokines</topic><topic>Dermatitis</topic><topic>Dermatitis - drug therapy</topic><topic>Dermatitis - etiology</topic><topic>Dermatitis - pathology</topic><topic>Dioxins</topic><topic>Disease</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Humans</topic><topic>Hyperplasia</topic><topic>Imiquimod</topic><topic>Imiquimod - toxicity</topic><topic>In vivo methods and tests</topic><topic>Inflammation</topic><topic>Inflammation - chemically induced</topic><topic>Inflammation - drug therapy</topic><topic>Inflammation - genetics</topic><topic>Inflammation - pathology</topic><topic>Inflammatory response</topic><topic>Keratinocytes</topic><topic>Keratinocytes - drug effects</topic><topic>Lesions</topic><topic>Markers</topic><topic>Mice</topic><topic>Molecular modelling</topic><topic>NAD(P)H oxidase</topic><topic>NADPH Oxidase 4 - genetics</topic><topic>NF-E2-Related Factor 2 - genetics</topic><topic>NOX4 protein</topic><topic>Oxidative stress</topic><topic>Pathogenesis</topic><topic>Phagocytosis</topic><topic>Polychlorinated Dibenzodioxins - toxicity</topic><topic>Psoriasis</topic><topic>Psoriasis - chemically induced</topic><topic>Psoriasis - drug therapy</topic><topic>Psoriasis - genetics</topic><topic>Psoriasis - pathology</topic><topic>Rapamycin</topic><topic>Receptors, Aryl Hydrocarbon - genetics</topic><topic>Sirolimus - pharmacology</topic><topic>Skin</topic><topic>Skin diseases</topic><topic>Skin lesions</topic><topic>Spleen</topic><topic>TCDD</topic><topic>TOR protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Hye Ran</creatorcontrib><creatorcontrib>Kim, Jin Cheol</creatorcontrib><creatorcontrib>Kang, Seok Young</creatorcontrib><creatorcontrib>Kim, Hye One</creatorcontrib><creatorcontrib>Park, Chun Wook</creatorcontrib><creatorcontrib>Chung, Bo Young</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Hye Ran</au><au>Kim, Jin Cheol</au><au>Kang, Seok Young</au><au>Kim, Hye One</au><au>Park, Chun Wook</au><au>Chung, Bo Young</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rapamycin Alleviates 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Aggravated Dermatitis in Mice with Imiquimod-Induced Psoriasis-Like Dermatitis by Inducing Autophagy</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2021-04-12</date><risdate>2021</risdate><volume>22</volume><issue>8</issue><spage>3968</spage><pages>3968-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Recently, the mTOR signaling has emerged as an important player in the pathogenesis of psoriasis. We previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced psoriatic skin inflammation was related to the inhibition of autophagy in keratinocytes. However, the effects and detailed molecular mechanisms of the mTOR inhibitor rapamycin and TCDD on psoriasis in vivo remain to be elucidated. In this study, we aimed to evaluate the effects of rapamycin and TCDD on skin lesions in imiquimod (IMQ)-induced psoriasis using a mouse model. TCDD aggravated skin inflammation in an IMQ-induced psoriatic mouse model. Furthermore, TCDD increased the expression of aryl hydrocarbon receptor (AHR), CYP1A1, proinflammatory cytokines, oxidative stress markers (NADPH oxidase (Nox) 2, Nox4), and phosphorylated P65NF-ĸB, whereas the expression of autophagy-related factors and the antioxidant marker nuclear factor-erythroid 2-related factor 2 (NRF2) decreased. Rapamycin reduced the aggravated skin inflammation induced by TCDD and restored TCDD-induced autophagy suppression and the increase of AHR expression, oxidative stress, and inflammatory response in the skin lesions of a psoriatic mouse model. In conclusion, we demonstrated that rapamycin alleviates TCDD-induced aggravated dermatitis in mice with imiquimod-induced psoriasis-like dermatitis through AHR and autophagy modulation.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>33921372</pmid><doi>10.3390/ijms22083968</doi><orcidid>https://orcid.org/0000-0002-2795-0140</orcidid><orcidid>https://orcid.org/0000-0002-1523-6951</orcidid><orcidid>https://orcid.org/0000-0001-6532-2244</orcidid><orcidid>https://orcid.org/0000-0001-7519-8910</orcidid><orcidid>https://orcid.org/0000-0001-5846-0008</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animals Antioxidants Antiviral drugs Autophagy Autophagy - drug effects Autophagy - genetics Cell Differentiation - drug effects Cells, Cultured Cytochrome P-450 CYP1A1 - genetics Cytochrome P450 Cytokines Dermatitis Dermatitis - drug therapy Dermatitis - etiology Dermatitis - pathology Dioxins Disease Gene Expression Regulation - drug effects Humans Hyperplasia Imiquimod Imiquimod - toxicity In vivo methods and tests Inflammation Inflammation - chemically induced Inflammation - drug therapy Inflammation - genetics Inflammation - pathology Inflammatory response Keratinocytes Keratinocytes - drug effects Lesions Markers Mice Molecular modelling NAD(P)H oxidase NADPH Oxidase 4 - genetics NF-E2-Related Factor 2 - genetics NOX4 protein Oxidative stress Pathogenesis Phagocytosis Polychlorinated Dibenzodioxins - toxicity Psoriasis Psoriasis - chemically induced Psoriasis - drug therapy Psoriasis - genetics Psoriasis - pathology Rapamycin Receptors, Aryl Hydrocarbon - genetics Sirolimus - pharmacology Skin Skin diseases Skin lesions Spleen TCDD TOR protein |
| title | Rapamycin Alleviates 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Aggravated Dermatitis in Mice with Imiquimod-Induced Psoriasis-Like Dermatitis by Inducing Autophagy |
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