Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters Staphylococcus aureus control
In atopic dermatitis (AD), lesional skin is frequently colonized by Staphylococcus aureus, which promotes clinical symptoms of the disease. The inflammatory milieu in the skin is characterized by a Th2 response, including M2 macrophages, which cannot eradicate S. aureus. Therefore, repolarization of...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-01-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1507989/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832583757916274688 |
|---|---|
| author | Christina Schmidt Kunjan Harit Stephan Traidl Michael Naumann Thomas Werfel Thomas Werfel Lennart M. Roesner Lennart M. Roesner Gopala Nishanth Dirk Schlüter Dirk Schlüter |
| author_facet | Christina Schmidt Kunjan Harit Stephan Traidl Michael Naumann Thomas Werfel Thomas Werfel Lennart M. Roesner Lennart M. Roesner Gopala Nishanth Dirk Schlüter Dirk Schlüter |
| author_sort | Christina Schmidt |
| collection | DOAJ |
| description | In atopic dermatitis (AD), lesional skin is frequently colonized by Staphylococcus aureus, which promotes clinical symptoms of the disease. The inflammatory milieu in the skin is characterized by a Th2 response, including M2 macrophages, which cannot eradicate S. aureus. Therefore, repolarization of macrophages toward the M1 phenotype may foster control of S. aureus. Our data show that the deubiquitinating enzyme cylindromatosis (CYLD) is strongly expressed in macrophages of AD patients and prevents the clearance of S. aureus. Mechanistically, CYLD impaired M1 macrophage polarization by K63-specific deubiquitination of STAT1 and activation of the NF-κB pathway via its interaction with TRAF6, NEMO, and RIPK2. Inhibition of STAT1 and NF-κB, independently, abolished the differences between S. aureus-infected CYLD-deficient and CYLD-competent M1 macrophages. Infection of Cyld-deficient and wild-type mice with S. aureus confirmed the protective CYLD function. Collectively, our study shows that CYLD impairs the control of S. aureus in macrophages of AD patients, identifying CYLD as a potential therapeutic target. |
| format | Article |
| id | doaj-art-fb7ec9ffddf24a5c9b3e814d1bf69987 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-fb7ec9ffddf24a5c9b3e814d1bf699872025-01-28T06:41:22ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011610.3389/fimmu.2025.15079891507989Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters Staphylococcus aureus controlChristina Schmidt0Kunjan Harit1Stephan Traidl2Michael Naumann3Thomas Werfel4Thomas Werfel5Lennart M. Roesner6Lennart M. Roesner7Gopala Nishanth8Dirk Schlüter9Dirk Schlüter10Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, GermanyInstitute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, GermanyDepartment of Dermatology and Allergy, Hannover Medical School, Hannover, GermanyInstitute of Experimental Internal Medicine, Otto-von-Guericke-University Magdeburg, Magdeburg, GermanyDepartment of Dermatology and Allergy, Hannover Medical School, Hannover, GermanyCluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, GermanyDepartment of Dermatology and Allergy, Hannover Medical School, Hannover, GermanyCluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, GermanyInstitute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, GermanyInstitute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, GermanyCluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, GermanyIn atopic dermatitis (AD), lesional skin is frequently colonized by Staphylococcus aureus, which promotes clinical symptoms of the disease. The inflammatory milieu in the skin is characterized by a Th2 response, including M2 macrophages, which cannot eradicate S. aureus. Therefore, repolarization of macrophages toward the M1 phenotype may foster control of S. aureus. Our data show that the deubiquitinating enzyme cylindromatosis (CYLD) is strongly expressed in macrophages of AD patients and prevents the clearance of S. aureus. Mechanistically, CYLD impaired M1 macrophage polarization by K63-specific deubiquitination of STAT1 and activation of the NF-κB pathway via its interaction with TRAF6, NEMO, and RIPK2. Inhibition of STAT1 and NF-κB, independently, abolished the differences between S. aureus-infected CYLD-deficient and CYLD-competent M1 macrophages. Infection of Cyld-deficient and wild-type mice with S. aureus confirmed the protective CYLD function. Collectively, our study shows that CYLD impairs the control of S. aureus in macrophages of AD patients, identifying CYLD as a potential therapeutic target.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1507989/fullStaphylococcus aureusmacrophageCYLDubiquitinatopic dermatitisSTAT1 |
| spellingShingle | Christina Schmidt Kunjan Harit Stephan Traidl Michael Naumann Thomas Werfel Thomas Werfel Lennart M. Roesner Lennart M. Roesner Gopala Nishanth Dirk Schlüter Dirk Schlüter Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters Staphylococcus aureus control Frontiers in Immunology Staphylococcus aureus macrophage CYLD ubiquitin atopic dermatitis STAT1 |
| title | Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters Staphylococcus aureus control |
| title_full | Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters Staphylococcus aureus control |
| title_fullStr | Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters Staphylococcus aureus control |
| title_full_unstemmed | Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters Staphylococcus aureus control |
| title_short | Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters Staphylococcus aureus control |
| title_sort | ablation of the deubiquitinating enzyme cylindromatosis cyld augments stat1 mediated m1 macrophage polarization and fosters staphylococcus aureus control |
| topic | Staphylococcus aureus macrophage CYLD ubiquitin atopic dermatitis STAT1 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1507989/full |
| work_keys_str_mv | AT christinaschmidt ablationofthedeubiquitinatingenzymecylindromatosiscyldaugmentsstat1mediatedm1macrophagepolarizationandfostersstaphylococcusaureuscontrol AT kunjanharit ablationofthedeubiquitinatingenzymecylindromatosiscyldaugmentsstat1mediatedm1macrophagepolarizationandfostersstaphylococcusaureuscontrol AT stephantraidl ablationofthedeubiquitinatingenzymecylindromatosiscyldaugmentsstat1mediatedm1macrophagepolarizationandfostersstaphylococcusaureuscontrol AT michaelnaumann ablationofthedeubiquitinatingenzymecylindromatosiscyldaugmentsstat1mediatedm1macrophagepolarizationandfostersstaphylococcusaureuscontrol AT thomaswerfel ablationofthedeubiquitinatingenzymecylindromatosiscyldaugmentsstat1mediatedm1macrophagepolarizationandfostersstaphylococcusaureuscontrol AT thomaswerfel ablationofthedeubiquitinatingenzymecylindromatosiscyldaugmentsstat1mediatedm1macrophagepolarizationandfostersstaphylococcusaureuscontrol AT lennartmroesner ablationofthedeubiquitinatingenzymecylindromatosiscyldaugmentsstat1mediatedm1macrophagepolarizationandfostersstaphylococcusaureuscontrol AT lennartmroesner ablationofthedeubiquitinatingenzymecylindromatosiscyldaugmentsstat1mediatedm1macrophagepolarizationandfostersstaphylococcusaureuscontrol AT gopalanishanth ablationofthedeubiquitinatingenzymecylindromatosiscyldaugmentsstat1mediatedm1macrophagepolarizationandfostersstaphylococcusaureuscontrol AT dirkschluter ablationofthedeubiquitinatingenzymecylindromatosiscyldaugmentsstat1mediatedm1macrophagepolarizationandfostersstaphylococcusaureuscontrol AT dirkschluter ablationofthedeubiquitinatingenzymecylindromatosiscyldaugmentsstat1mediatedm1macrophagepolarizationandfostersstaphylococcusaureuscontrol |