The PYRIN domain is required for TLR4-mediated inflammation by PYHIN family members
Summary: Innate immunity relies on pattern recognition receptors (PRRs) to detect threats, including pathogens and damage-associated molecular patterns (DAMPs) from damaged cells. IFI16 behaves as a DAMP and activates Toll-like receptor 4 (TLR4)-mediated inflammation. Here, we identify the N-termina...
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| Language: | English |
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Elsevier
2025-05-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225006741 |
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| author | Andrea Iannucci Davide Lacarbonara Valeria Caneparo Federica Castiglioni Andrea Butticè Stefano Raviola Chiara Porta Riccardo Miggiano Ivan Zanoni Marisa Gariglio Marco De Andrea |
| author_facet | Andrea Iannucci Davide Lacarbonara Valeria Caneparo Federica Castiglioni Andrea Butticè Stefano Raviola Chiara Porta Riccardo Miggiano Ivan Zanoni Marisa Gariglio Marco De Andrea |
| author_sort | Andrea Iannucci |
| collection | DOAJ |
| description | Summary: Innate immunity relies on pattern recognition receptors (PRRs) to detect threats, including pathogens and damage-associated molecular patterns (DAMPs) from damaged cells. IFI16 behaves as a DAMP and activates Toll-like receptor 4 (TLR4)-mediated inflammation. Here, we identify the N-terminal PYRIN domain (PYD) of IFI16 as critical for binding TLR4 and triggering inflammation, and we confirm this interaction through in vitro and in vivo assays. The inflammatory activity of IFI16PYD is unique to human and mouse PYHIN proteins, as PYDs in other proteins, such as NLRP3 or ASC, do not activate TLR4. Disrupting the IFI16-TLR4 interaction prevents pro-inflammatory cytokine production, reducing immune cell recruitment and skin fibrosis in mice. Elevated IFI16 and TLR4 levels in systemic sclerosis patients suggest a role in disease progression. These findings provide insight into DAMP recognition and inflammation propagation, highlighting the IFI16-TLR4 interaction as a potential therapeutic target for sterile inflammatory diseases. |
| format | Article |
| id | doaj-art-d02af35df8fb4db1a834010a3d25b623 |
| institution | OA Journals |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-d02af35df8fb4db1a834010a3d25b6232025-08-20T01:47:28ZengElsevieriScience2589-00422025-05-0128511241310.1016/j.isci.2025.112413The PYRIN domain is required for TLR4-mediated inflammation by PYHIN family membersAndrea Iannucci0Davide Lacarbonara1Valeria Caneparo2Federica Castiglioni3Andrea Butticè4Stefano Raviola5Chiara Porta6Riccardo Miggiano7Ivan Zanoni8Marisa Gariglio9Marco De Andrea10CAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy; Division of Immunology, Harvard Medical School, and Boston Children’s Hospital, Boston, MA 02115, USACAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, ItalyCAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, ItalyCAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy; Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, ItalyDepartment of Pharmaceutical Sciences, University of Eastern Piedmont, 28100 Novara, ItalyCAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy; Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, ItalyCAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy; Department of Pharmaceutical Sciences, University of Eastern Piedmont, 28100 Novara, ItalyDepartment of Pharmaceutical Sciences, University of Eastern Piedmont, 28100 Novara, ItalyDivision of Immunology, Harvard Medical School, and Boston Children’s Hospital, Boston, MA 02115, USA; Division of Gastroenterology, Harvard Medical School, and Boston Children’s Hospital, Boston, MA 02115, USACAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy; Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, ItalyCAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy; Department of Public Health and Pediatric Sciences, University of Turin, Medical School, 10126 Turin, Italy; Corresponding authorSummary: Innate immunity relies on pattern recognition receptors (PRRs) to detect threats, including pathogens and damage-associated molecular patterns (DAMPs) from damaged cells. IFI16 behaves as a DAMP and activates Toll-like receptor 4 (TLR4)-mediated inflammation. Here, we identify the N-terminal PYRIN domain (PYD) of IFI16 as critical for binding TLR4 and triggering inflammation, and we confirm this interaction through in vitro and in vivo assays. The inflammatory activity of IFI16PYD is unique to human and mouse PYHIN proteins, as PYDs in other proteins, such as NLRP3 or ASC, do not activate TLR4. Disrupting the IFI16-TLR4 interaction prevents pro-inflammatory cytokine production, reducing immune cell recruitment and skin fibrosis in mice. Elevated IFI16 and TLR4 levels in systemic sclerosis patients suggest a role in disease progression. These findings provide insight into DAMP recognition and inflammation propagation, highlighting the IFI16-TLR4 interaction as a potential therapeutic target for sterile inflammatory diseases.http://www.sciencedirect.com/science/article/pii/S2589004225006741Molecular biologyImmune responseStructural biology |
| spellingShingle | Andrea Iannucci Davide Lacarbonara Valeria Caneparo Federica Castiglioni Andrea Butticè Stefano Raviola Chiara Porta Riccardo Miggiano Ivan Zanoni Marisa Gariglio Marco De Andrea The PYRIN domain is required for TLR4-mediated inflammation by PYHIN family members iScience Molecular biology Immune response Structural biology |
| title | The PYRIN domain is required for TLR4-mediated inflammation by PYHIN family members |
| title_full | The PYRIN domain is required for TLR4-mediated inflammation by PYHIN family members |
| title_fullStr | The PYRIN domain is required for TLR4-mediated inflammation by PYHIN family members |
| title_full_unstemmed | The PYRIN domain is required for TLR4-mediated inflammation by PYHIN family members |
| title_short | The PYRIN domain is required for TLR4-mediated inflammation by PYHIN family members |
| title_sort | pyrin domain is required for tlr4 mediated inflammation by pyhin family members |
| topic | Molecular biology Immune response Structural biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225006741 |
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