NF-κB c-Rel is a critical regulator of TLR7-induced inflammation in psoriasisResearch in context
Summary: Background: Nuclear factor kappa B (NF-κB) c-Rel is a psoriasis susceptibility locus, however mechanisms underlying c-Rel transactivation during disease are poorly understood. Inflammation in psoriasis can be triggered following Toll-like Receptor 7 (TLR7) signalling in dendritic cells (DC...
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Elsevier
2024-12-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396424004882 |
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| author | Angela Rose Liu Nandini Sarkar Jordan D. Cress Tristan J. de Jesus Ananya Vadlakonda Joshua T. Centore Alexis D. Griffith Bethany Rohr Thomas S. McCormick Kevin D. Cooper Parameswaran Ramakrishnan |
| author_facet | Angela Rose Liu Nandini Sarkar Jordan D. Cress Tristan J. de Jesus Ananya Vadlakonda Joshua T. Centore Alexis D. Griffith Bethany Rohr Thomas S. McCormick Kevin D. Cooper Parameswaran Ramakrishnan |
| author_sort | Angela Rose Liu |
| collection | DOAJ |
| description | Summary: Background: Nuclear factor kappa B (NF-κB) c-Rel is a psoriasis susceptibility locus, however mechanisms underlying c-Rel transactivation during disease are poorly understood. Inflammation in psoriasis can be triggered following Toll-like Receptor 7 (TLR7) signalling in dendritic cells (DCs), and c-Rel is a critical regulator of DC function. Here, we studied the mechanism of TLR7-induced c-Rel-mediated inflammation in DCs. Methods: The overall expression of c-Rel was analysed in skin sections from patients with psoriasis in human transcriptomics datasets as well as the imiquimod-induced psoriasis mouse model. The function of c-Rel in DCs following TLR7 stimulation was determined by c-Rel CRISPR/Cas9 knockout DC2.4 immortalised cells and primary bone marrow derived dendritic cells from c-Rel knockout C57BL6/J mice. Findings: c-Rel is highly expressed in lesional skin of patients with psoriasis and TLR7-induced psoriatic lesions in mice. c-Rel deficiency protected mice from the disease, and specifically compromised TLR7-induced, and not TLR9- or TLR3-induced, inflammation in dendritic cells. Mechanistically, c-Rel deficiency disrupted activating NF-κB dimers and allowed binding of inhibitory NF-κB homodimers to the IL-1β and IL-6 promoters thus inhibiting their expression. This functionally compromises the ability of c-Rel deficient DCs to induce Th17 polarisation, which is critical in psoriasis pathogenesis. Interpretation: Our findings reveal that c-Rel is a key regulator of TLR7-mediated dendritic cell-dependent inflammation, and that targeting c-Rel-dependent signalling could prove an effective strategy to dampen excessive inflammation in TLR7-related skin inflammation. Funding: A complete list of funding sources that contributed to this study can be found in the Acknowledgements section. |
| format | Article |
| id | doaj-art-50d8c9876c9a43f7bbc4b068aa7dd51a |
| institution | OA Journals |
| issn | 2352-3964 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
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| series | EBioMedicine |
| spelling | doaj-art-50d8c9876c9a43f7bbc4b068aa7dd51a2025-08-20T01:53:22ZengElsevierEBioMedicine2352-39642024-12-0111010545210.1016/j.ebiom.2024.105452NF-κB c-Rel is a critical regulator of TLR7-induced inflammation in psoriasisResearch in contextAngela Rose Liu0Nandini Sarkar1Jordan D. Cress2Tristan J. de Jesus3Ananya Vadlakonda4Joshua T. Centore5Alexis D. Griffith6Bethany Rohr7Thomas S. McCormick8Kevin D. Cooper9Parameswaran Ramakrishnan10Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USADepartment of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USADepartment of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USADepartment of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USADepartment of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USADepartment of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USADepartment of Dermatology, Case Western Reserve University, 2109 Adelbert Road, Cleveland, Ohio 44106, USADepartment of Dermatology, Case Western Reserve University, 2109 Adelbert Road, Cleveland, Ohio 44106, USA; University Hospitals-Cleveland Medical Center, 11100 Euclid Ave, Cleveland, Ohio 44106, USADepartment of Dermatology, Case Western Reserve University, 2109 Adelbert Road, Cleveland, Ohio 44106, USA; University Hospitals-Cleveland Medical Center, 11100 Euclid Ave, Cleveland, Ohio 44106, USADepartment of Dermatology, Case Western Reserve University, 2109 Adelbert Road, Cleveland, Ohio 44106, USA; University Hospitals-Cleveland Medical Center, 11100 Euclid Ave, Cleveland, Ohio 44106, USADepartment of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USA; The Case Comprehensive Cancer Center, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USA; Department of Biochemistry, Case Western Reserve University, 2109 Adelbert Road, Cleveland, Ohio 44106, USA; University Hospitals-Cleveland Medical Center, 11100 Euclid Ave, Cleveland, Ohio 44106, USA; Louis Stokes Veterans Affairs Medical Center, 10701 East Blvd, Cleveland, Ohio 44106, USA; Corresponding author. Department of Pathology, School of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, 6526, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106, USA.Summary: Background: Nuclear factor kappa B (NF-κB) c-Rel is a psoriasis susceptibility locus, however mechanisms underlying c-Rel transactivation during disease are poorly understood. Inflammation in psoriasis can be triggered following Toll-like Receptor 7 (TLR7) signalling in dendritic cells (DCs), and c-Rel is a critical regulator of DC function. Here, we studied the mechanism of TLR7-induced c-Rel-mediated inflammation in DCs. Methods: The overall expression of c-Rel was analysed in skin sections from patients with psoriasis in human transcriptomics datasets as well as the imiquimod-induced psoriasis mouse model. The function of c-Rel in DCs following TLR7 stimulation was determined by c-Rel CRISPR/Cas9 knockout DC2.4 immortalised cells and primary bone marrow derived dendritic cells from c-Rel knockout C57BL6/J mice. Findings: c-Rel is highly expressed in lesional skin of patients with psoriasis and TLR7-induced psoriatic lesions in mice. c-Rel deficiency protected mice from the disease, and specifically compromised TLR7-induced, and not TLR9- or TLR3-induced, inflammation in dendritic cells. Mechanistically, c-Rel deficiency disrupted activating NF-κB dimers and allowed binding of inhibitory NF-κB homodimers to the IL-1β and IL-6 promoters thus inhibiting their expression. This functionally compromises the ability of c-Rel deficient DCs to induce Th17 polarisation, which is critical in psoriasis pathogenesis. Interpretation: Our findings reveal that c-Rel is a key regulator of TLR7-mediated dendritic cell-dependent inflammation, and that targeting c-Rel-dependent signalling could prove an effective strategy to dampen excessive inflammation in TLR7-related skin inflammation. Funding: A complete list of funding sources that contributed to this study can be found in the Acknowledgements section.http://www.sciencedirect.com/science/article/pii/S2352396424004882TLR7NF-κB c-RelInflammationPsoriasisTranscription |
| spellingShingle | Angela Rose Liu Nandini Sarkar Jordan D. Cress Tristan J. de Jesus Ananya Vadlakonda Joshua T. Centore Alexis D. Griffith Bethany Rohr Thomas S. McCormick Kevin D. Cooper Parameswaran Ramakrishnan NF-κB c-Rel is a critical regulator of TLR7-induced inflammation in psoriasisResearch in context EBioMedicine TLR7 NF-κB c-Rel Inflammation Psoriasis Transcription |
| title | NF-κB c-Rel is a critical regulator of TLR7-induced inflammation in psoriasisResearch in context |
| title_full | NF-κB c-Rel is a critical regulator of TLR7-induced inflammation in psoriasisResearch in context |
| title_fullStr | NF-κB c-Rel is a critical regulator of TLR7-induced inflammation in psoriasisResearch in context |
| title_full_unstemmed | NF-κB c-Rel is a critical regulator of TLR7-induced inflammation in psoriasisResearch in context |
| title_short | NF-κB c-Rel is a critical regulator of TLR7-induced inflammation in psoriasisResearch in context |
| title_sort | nf κb c rel is a critical regulator of tlr7 induced inflammation in psoriasisresearch in context |
| topic | TLR7 NF-κB c-Rel Inflammation Psoriasis Transcription |
| url | http://www.sciencedirect.com/science/article/pii/S2352396424004882 |
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