Inflammation dependent mTORC1 signaling interferes with the switch from keratinocyte proliferation to differentiation
Psoriasis is a frequent and often severe inflammatory skin disease, characterized by altered epidermal homeostasis. Since we found previously that Akt/mTOR signaling is hyperactivated in psoriatic skin, we aimed at elucidating the role of aberrant mTORC1 signaling in this disease. We found that unde...
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| Veröffentlicht in: | PloS one 2017-07, Vol.12 (7), p.e0180853-e0180853 |
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| creator | Buerger, Claudia Shirsath, Nitesh Lang, Victoria Berard, Alina Diehl, Sandra Kaufmann, Roland Boehncke, Wolf-Henning Wolf, Peter |
| description | Psoriasis is a frequent and often severe inflammatory skin disease, characterized by altered epidermal homeostasis. Since we found previously that Akt/mTOR signaling is hyperactivated in psoriatic skin, we aimed at elucidating the role of aberrant mTORC1 signaling in this disease. We found that under healthy conditions mTOR signaling was shut off when keratinocytes switch from proliferation to terminal differentiation. Inflammatory cytokines (IL-1β, IL-17A, TNF-α) induced aberrant mTOR activity which led to enhanced proliferation and reduced expression of differentiation markers. Conversely, regular differentiation could be restored if mTORC1 signaling was blocked. In mice, activation of mTOR through the agonist MHY1485 also led to aberrant epidermal organization and involucrin distribution. In summary, these results not only identify mTORC1 as an important signal integrator pivotal for the cells fate to either proliferate or differentiate, but emphasize the role of inflammation-dependent mTOR activation as a psoriatic pathomechanism. |
| doi_str_mv | 10.1371/journal.pone.0180853 |
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Since we found previously that Akt/mTOR signaling is hyperactivated in psoriatic skin, we aimed at elucidating the role of aberrant mTORC1 signaling in this disease. We found that under healthy conditions mTOR signaling was shut off when keratinocytes switch from proliferation to terminal differentiation. Inflammatory cytokines (IL-1β, IL-17A, TNF-α) induced aberrant mTOR activity which led to enhanced proliferation and reduced expression of differentiation markers. Conversely, regular differentiation could be restored if mTORC1 signaling was blocked. In mice, activation of mTOR through the agonist MHY1485 also led to aberrant epidermal organization and involucrin distribution. In summary, these results not only identify mTORC1 as an important signal integrator pivotal for the cells fate to either proliferate or differentiate, but emphasize the role of inflammation-dependent mTOR activation as a psoriatic pathomechanism.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0180853</identifier><identifier>PMID: 28700632</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aberration ; Activation ; Adolescent ; Adult ; Aged ; AKT protein ; Animals ; Biology and Life Sciences ; Cell Differentiation - genetics ; Cell Differentiation - physiology ; Cell Line ; Cell Proliferation - genetics ; Cell Proliferation - physiology ; Collagen ; Cytokines ; Dermatology ; Differentiation ; Female ; Gene expression ; Homeostasis ; Humans ; Immunoassay ; Immunohistochemistry ; Interleukin 1 ; Keratin ; Keratinocytes ; Keratinocytes - metabolism ; Keratinocytes - physiology ; Kinases ; Male ; Markers ; Mechanistic Target of Rapamycin Complex 1 ; Medicine and Health Sciences ; Mice ; Mice, Inbred BALB C ; Middle Aged ; Multiprotein Complexes - genetics ; Multiprotein Complexes - metabolism ; Pathogenesis ; Phosphorylation ; Proteins ; Psoriasis ; Research and Analysis Methods ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Small Interfering - genetics ; Signal Transduction - genetics ; Signal Transduction - physiology ; Skin diseases ; TOR protein ; TOR Serine-Threonine Kinases - genetics ; TOR Serine-Threonine Kinases - metabolism ; Tumor necrosis factor ; Young Adult</subject><ispartof>PloS one, 2017-07, Vol.12 (7), p.e0180853-e0180853</ispartof><rights>2017 Buerger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Buerger et al 2017 Buerger et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-a8fdeaf622fece86904b38e2b7b00b5151aa6de7632b4a1c5365f9879d1541353</citedby><cites>FETCH-LOGICAL-c526t-a8fdeaf622fece86904b38e2b7b00b5151aa6de7632b4a1c5365f9879d1541353</cites><orcidid>0000-0002-7838-197X</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/PMC5507280/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507280/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28700632$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Blumenberg, Miroslav</contributor><creatorcontrib>Buerger, Claudia</creatorcontrib><creatorcontrib>Shirsath, Nitesh</creatorcontrib><creatorcontrib>Lang, Victoria</creatorcontrib><creatorcontrib>Berard, Alina</creatorcontrib><creatorcontrib>Diehl, Sandra</creatorcontrib><creatorcontrib>Kaufmann, Roland</creatorcontrib><creatorcontrib>Boehncke, Wolf-Henning</creatorcontrib><creatorcontrib>Wolf, Peter</creatorcontrib><title>Inflammation dependent mTORC1 signaling interferes with the switch from keratinocyte proliferation to differentiation</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Psoriasis is a frequent and often severe inflammatory skin disease, characterized by altered epidermal homeostasis. Since we found previously that Akt/mTOR signaling is hyperactivated in psoriatic skin, we aimed at elucidating the role of aberrant mTORC1 signaling in this disease. We found that under healthy conditions mTOR signaling was shut off when keratinocytes switch from proliferation to terminal differentiation. Inflammatory cytokines (IL-1β, IL-17A, TNF-α) induced aberrant mTOR activity which led to enhanced proliferation and reduced expression of differentiation markers. Conversely, regular differentiation could be restored if mTORC1 signaling was blocked. In mice, activation of mTOR through the agonist MHY1485 also led to aberrant epidermal organization and involucrin distribution. In summary, these results not only identify mTORC1 as an important signal integrator pivotal for the cells fate to either proliferate or differentiate, but emphasize the role of inflammation-dependent mTOR activation as a psoriatic pathomechanism.</description><subject>Aberration</subject><subject>Activation</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Biology and Life Sciences</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Differentiation - physiology</subject><subject>Cell Line</subject><subject>Cell Proliferation - genetics</subject><subject>Cell Proliferation - physiology</subject><subject>Collagen</subject><subject>Cytokines</subject><subject>Dermatology</subject><subject>Differentiation</subject><subject>Female</subject><subject>Gene expression</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Immunoassay</subject><subject>Immunohistochemistry</subject><subject>Interleukin 1</subject><subject>Keratin</subject><subject>Keratinocytes</subject><subject>Keratinocytes - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Buerger, Claudia</au><au>Shirsath, Nitesh</au><au>Lang, Victoria</au><au>Berard, Alina</au><au>Diehl, Sandra</au><au>Kaufmann, Roland</au><au>Boehncke, Wolf-Henning</au><au>Wolf, Peter</au><au>Blumenberg, Miroslav</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inflammation dependent mTORC1 signaling interferes with the switch from keratinocyte proliferation to differentiation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-07-10</date><risdate>2017</risdate><volume>12</volume><issue>7</issue><spage>e0180853</spage><epage>e0180853</epage><pages>e0180853-e0180853</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Psoriasis is a frequent and often severe inflammatory skin disease, characterized by altered epidermal homeostasis. Since we found previously that Akt/mTOR signaling is hyperactivated in psoriatic skin, we aimed at elucidating the role of aberrant mTORC1 signaling in this disease. We found that under healthy conditions mTOR signaling was shut off when keratinocytes switch from proliferation to terminal differentiation. Inflammatory cytokines (IL-1β, IL-17A, TNF-α) induced aberrant mTOR activity which led to enhanced proliferation and reduced expression of differentiation markers. Conversely, regular differentiation could be restored if mTORC1 signaling was blocked. In mice, activation of mTOR through the agonist MHY1485 also led to aberrant epidermal organization and involucrin distribution. In summary, these results not only identify mTORC1 as an important signal integrator pivotal for the cells fate to either proliferate or differentiate, but emphasize the role of inflammation-dependent mTOR activation as a psoriatic pathomechanism.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28700632</pmid><doi>10.1371/journal.pone.0180853</doi><orcidid>https://orcid.org/0000-0002-7838-197X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Aberration Activation Adolescent Adult Aged AKT protein Animals Biology and Life Sciences Cell Differentiation - genetics Cell Differentiation - physiology Cell Line Cell Proliferation - genetics Cell Proliferation - physiology Collagen Cytokines Dermatology Differentiation Female Gene expression Homeostasis Humans Immunoassay Immunohistochemistry Interleukin 1 Keratin Keratinocytes Keratinocytes - metabolism Keratinocytes - physiology Kinases Male Markers Mechanistic Target of Rapamycin Complex 1 Medicine and Health Sciences Mice Mice, Inbred BALB C Middle Aged Multiprotein Complexes - genetics Multiprotein Complexes - metabolism Pathogenesis Phosphorylation Proteins Psoriasis Research and Analysis Methods Reverse Transcriptase Polymerase Chain Reaction RNA, Small Interfering - genetics Signal Transduction - genetics Signal Transduction - physiology Skin diseases TOR protein TOR Serine-Threonine Kinases - genetics TOR Serine-Threonine Kinases - metabolism Tumor necrosis factor Young Adult |
| title | Inflammation dependent mTORC1 signaling interferes with the switch from keratinocyte proliferation to differentiation |
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