Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression
Impaired wound healing associated with recurrent Staphylococcus aureus infection and unresolved inflammation are hallmarks of nonhealing diabetic foot ulcers (DFUs). Perforin-2, an innate immunity molecule against intracellular bacteria, limits cutaneous infection and dissemination of S. aureus in m...
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| Veröffentlicht in: | The Journal of clinical investigation 2021-12, Vol.131 (24), p.0_1-10 |
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| creator | Pastar, Irena Sawaya, Andrew P Marjanovic, Jelena Burgess, Jamie L Strbo, Natasa Rivas, Katelyn E Wikramanayake, Tongyu C Head, Cheyanne R Stone, Rivka C Jozic, Ivan Stojadinovic, Olivera Kornfeld, Eran Y Kirsner, Robert S Lev-Tov, Hadar Tomic-Canic, Marjana |
| description | Impaired wound healing associated with recurrent Staphylococcus aureus infection and unresolved inflammation are hallmarks of nonhealing diabetic foot ulcers (DFUs). Perforin-2, an innate immunity molecule against intracellular bacteria, limits cutaneous infection and dissemination of S. aureus in mice. Here, we report the intracellular accumulation of S. aureus in the epidermis of DFUs with no clinical signs of infection due to marked suppression of perforin-2. S. aureus residing within the epidermis of DFUs triggers AIM2 inflammasome activation and pyroptosis. These findings were corroborated in mice lacking perforin-2. The effects of pyroptosis on DFU clinical outcomes were further elucidated in a 4-week longitudinal clinical study in patients with DFUs receiving standard care. Increased AIM2 inflammasome and ASC-pyroptosome coupled with induction of IL-1ß were found in nonhealing DFUs compared with healing DFUs. Our findings revealed that perforin-2 suppression, intracellular S. aureus accumulation, and associated induction of pyroptosis contribute to healing inhibition and prolonged inflammation in patients with DFUs. |
| doi_str_mv | 10.1172/JCM33727 |
| format | Article |
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Perforin-2, an innate immunity molecule against intracellular bacteria, limits cutaneous infection and dissemination of S. aureus in mice. Here, we report the intracellular accumulation of S. aureus in the epidermis of DFUs with no clinical signs of infection due to marked suppression of perforin-2. S. aureus residing within the epidermis of DFUs triggers AIM2 inflammasome activation and pyroptosis. These findings were corroborated in mice lacking perforin-2. The effects of pyroptosis on DFU clinical outcomes were further elucidated in a 4-week longitudinal clinical study in patients with DFUs receiving standard care. Increased AIM2 inflammasome and ASC-pyroptosome coupled with induction of IL-1ß were found in nonhealing DFUs compared with healing DFUs. Our findings revealed that perforin-2 suppression, intracellular S. aureus accumulation, and associated induction of pyroptosis contribute to healing inhibition and prolonged inflammation in patients with DFUs.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCM33727</identifier><language>eng</language><publisher>Ann Arbor: American Society for Clinical Investigation</publisher><subject>Apoptosis ; Bacteria ; Biomedical research ; Diabetes ; Diabetes mellitus ; Epidermis ; Foot diseases ; Histology ; Inflammasomes ; Inflammation ; Innate immunity ; Intracellular ; Leg ulcers ; Microscopy ; Pathogens ; Patients ; Penicillin ; Perforin ; Proteins ; Pyroptosis ; Recurrent infection ; Staphylococcus aureus ; Staphylococcus infections ; Ulcers ; Wound healing</subject><ispartof>The Journal of clinical investigation, 2021-12, Vol.131 (24), p.0_1-10</ispartof><rights>Copyright American Society for Clinical Investigation Dec 2021</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Pastar, Irena</creatorcontrib><creatorcontrib>Sawaya, Andrew P</creatorcontrib><creatorcontrib>Marjanovic, Jelena</creatorcontrib><creatorcontrib>Burgess, Jamie L</creatorcontrib><creatorcontrib>Strbo, Natasa</creatorcontrib><creatorcontrib>Rivas, Katelyn E</creatorcontrib><creatorcontrib>Wikramanayake, Tongyu C</creatorcontrib><creatorcontrib>Head, Cheyanne R</creatorcontrib><creatorcontrib>Stone, Rivka C</creatorcontrib><creatorcontrib>Jozic, Ivan</creatorcontrib><creatorcontrib>Stojadinovic, Olivera</creatorcontrib><creatorcontrib>Kornfeld, Eran Y</creatorcontrib><creatorcontrib>Kirsner, Robert S</creatorcontrib><creatorcontrib>Lev-Tov, Hadar</creatorcontrib><creatorcontrib>Tomic-Canic, Marjana</creatorcontrib><title>Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression</title><title>The Journal of clinical investigation</title><description>Impaired wound healing associated with recurrent Staphylococcus aureus infection and unresolved inflammation are hallmarks of nonhealing diabetic foot ulcers (DFUs). Perforin-2, an innate immunity molecule against intracellular bacteria, limits cutaneous infection and dissemination of S. aureus in mice. Here, we report the intracellular accumulation of S. aureus in the epidermis of DFUs with no clinical signs of infection due to marked suppression of perforin-2. S. aureus residing within the epidermis of DFUs triggers AIM2 inflammasome activation and pyroptosis. These findings were corroborated in mice lacking perforin-2. The effects of pyroptosis on DFU clinical outcomes were further elucidated in a 4-week longitudinal clinical study in patients with DFUs receiving standard care. Increased AIM2 inflammasome and ASC-pyroptosome coupled with induction of IL-1ß were found in nonhealing DFUs compared with healing DFUs. Our findings revealed that perforin-2 suppression, intracellular S. aureus accumulation, and associated induction of pyroptosis contribute to healing inhibition and prolonged inflammation in patients with DFUs.</description><subject>Apoptosis</subject><subject>Bacteria</subject><subject>Biomedical research</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Epidermis</subject><subject>Foot diseases</subject><subject>Histology</subject><subject>Inflammasomes</subject><subject>Inflammation</subject><subject>Innate immunity</subject><subject>Intracellular</subject><subject>Leg ulcers</subject><subject>Microscopy</subject><subject>Pathogens</subject><subject>Patients</subject><subject>Penicillin</subject><subject>Perforin</subject><subject>Proteins</subject><subject>Pyroptosis</subject><subject>Recurrent infection</subject><subject>Staphylococcus aureus</subject><subject>Staphylococcus infections</subject><subject>Ulcers</subject><subject>Wound healing</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNj71KBDEURoMoOP6AjxCwHs3PjBPrRVHBSvslm70zkyXkxpuk2MZnN4IPYHWKc77iY-xGijspJ3X_tnnXelLTCevkOJreKG1OWSeEkv3jpM05u8j5IIQchnHo2PdrLGQdhFCDJf5RbFqPAR06VzO3laChkF8WoMzTkTAVzL6puOcO29jvaoHWIPdx9TtfPEaOM1_BBh8Xvq_wKxPQjORjr3iuKRHk3MIrdjbbkOH6j5fs9vnpc_PSJ8KvCrlsD1gpNrVVD0oZqdsR_b_qB6k2Vpg</recordid><startdate>20211201</startdate><enddate>20211201</enddate><creator>Pastar, Irena</creator><creator>Sawaya, Andrew P</creator><creator>Marjanovic, Jelena</creator><creator>Burgess, Jamie L</creator><creator>Strbo, Natasa</creator><creator>Rivas, Katelyn E</creator><creator>Wikramanayake, Tongyu 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Strbo, Natasa ; Rivas, Katelyn E ; Wikramanayake, Tongyu C ; Head, Cheyanne R ; Stone, Rivka C ; Jozic, Ivan ; Stojadinovic, Olivera ; Kornfeld, Eran Y ; Kirsner, Robert S ; Lev-Tov, Hadar ; Tomic-Canic, Marjana</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_journals_26228130023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Apoptosis</topic><topic>Bacteria</topic><topic>Biomedical research</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Epidermis</topic><topic>Foot diseases</topic><topic>Histology</topic><topic>Inflammasomes</topic><topic>Inflammation</topic><topic>Innate immunity</topic><topic>Intracellular</topic><topic>Leg ulcers</topic><topic>Microscopy</topic><topic>Pathogens</topic><topic>Patients</topic><topic>Penicillin</topic><topic>Perforin</topic><topic>Proteins</topic><topic>Pyroptosis</topic><topic>Recurrent 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Central China</collection><collection>SIRS Editorial</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pastar, Irena</au><au>Sawaya, Andrew P</au><au>Marjanovic, Jelena</au><au>Burgess, Jamie L</au><au>Strbo, Natasa</au><au>Rivas, Katelyn E</au><au>Wikramanayake, Tongyu C</au><au>Head, Cheyanne R</au><au>Stone, Rivka C</au><au>Jozic, Ivan</au><au>Stojadinovic, Olivera</au><au>Kornfeld, Eran Y</au><au>Kirsner, Robert S</au><au>Lev-Tov, Hadar</au><au>Tomic-Canic, Marjana</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression</atitle><jtitle>The Journal of clinical investigation</jtitle><date>2021-12-01</date><risdate>2021</risdate><volume>131</volume><issue>24</issue><spage>0_1</spage><epage>10</epage><pages>0_1-10</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Impaired wound healing associated with recurrent Staphylococcus aureus infection and unresolved inflammation are hallmarks of nonhealing diabetic foot ulcers (DFUs). Perforin-2, an innate immunity molecule against intracellular bacteria, limits cutaneous infection and dissemination of S. aureus in mice. Here, we report the intracellular accumulation of S. aureus in the epidermis of DFUs with no clinical signs of infection due to marked suppression of perforin-2. S. aureus residing within the epidermis of DFUs triggers AIM2 inflammasome activation and pyroptosis. These findings were corroborated in mice lacking perforin-2. The effects of pyroptosis on DFU clinical outcomes were further elucidated in a 4-week longitudinal clinical study in patients with DFUs receiving standard care. Increased AIM2 inflammasome and ASC-pyroptosome coupled with induction of IL-1ß were found in nonhealing DFUs compared with healing DFUs. Our findings revealed that perforin-2 suppression, intracellular S. aureus accumulation, and associated induction of pyroptosis contribute to healing inhibition and prolonged inflammation in patients with DFUs.</abstract><cop>Ann Arbor</cop><pub>American Society for Clinical Investigation</pub><doi>10.1172/JCM33727</doi></addata></record> |
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| subjects | Apoptosis Bacteria Biomedical research Diabetes Diabetes mellitus Epidermis Foot diseases Histology Inflammasomes Inflammation Innate immunity Intracellular Leg ulcers Microscopy Pathogens Patients Penicillin Perforin Proteins Pyroptosis Recurrent infection Staphylococcus aureus Staphylococcus infections Ulcers Wound healing |
| title | Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression |
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