The trapping of live neutrophils by macrophages during infection
Abstract Neutrophils are highly abundant in the oral mucosal tissues, and their balanced activation and clearance are essential for immune homeostasis. Here, we demonstrate that neutrophils infected with the bacterial pathogen Porphyromonas gingivalis (Pg) are captured alive by macrophages in a mann...
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| Format: | Article |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07808-5 |
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| author | Kelley N. Cooper Marina Terekhova Barbara Potempa Ana D’Aubeterre Jerome Timbol Si An Chen Antoine Dufour Shunying Jin Maxim N. Artyomov Jan Potempa Juhi Bagaitkar |
| author_facet | Kelley N. Cooper Marina Terekhova Barbara Potempa Ana D’Aubeterre Jerome Timbol Si An Chen Antoine Dufour Shunying Jin Maxim N. Artyomov Jan Potempa Juhi Bagaitkar |
| author_sort | Kelley N. Cooper |
| collection | DOAJ |
| description | Abstract Neutrophils are highly abundant in the oral mucosal tissues, and their balanced activation and clearance are essential for immune homeostasis. Here, we demonstrate that neutrophils infected with the bacterial pathogen Porphyromonas gingivalis (Pg) are captured alive by macrophages in a manner that bypasses all known receptor-ligand interactions involved in the phagocytosis of either live or dead cells. Mechanistically, upon interaction with Pg, or its protease RgpB (gingipains), live neutrophils undergo rapid remodeling of their proteomes, generating neoepitopes. N-terminomics-based proteomic profiling identified multiple RgpB cleavage sites on several azurophilic granule proteins that are translocated to the surface of live neutrophils via low-level degranulation and activate macrophage αMβ2 integrin receptors, thus mediating internalization of non-apoptotic neutrophils within macrophage phagosomes. Macrophages with entrapped live neutrophils exhibit phenotypic and transcriptional reprogramming, consistent with inflammatory outcomes in vitro and in vivo. In contrast to the immunosuppressive outcomes associated with efferocytosis of apoptotic neutrophils, live neutrophil entrapment failed to fully activate several catabolic and metabolic processes and exhibited a defective activation of PPAR-γ mediated pro-resolution pathways, thereby promoting bacterial persistence and hindering the resolution of inflammation. Thus, our data demonstrate a novel immune subversion strategy unique to Pg and reveal a previously unknown mode of live neutrophil sequestration into macrophages during an infection. |
| format | Article |
| id | doaj-art-a19583213b874ecdb5017635daedb865 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-a19583213b874ecdb5017635daedb8652025-08-20T04:01:40ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111410.1038/s41419-025-07808-5The trapping of live neutrophils by macrophages during infectionKelley N. Cooper0Marina Terekhova1Barbara Potempa2Ana D’Aubeterre3Jerome Timbol4Si An Chen5Antoine Dufour6Shunying Jin7Maxim N. Artyomov8Jan Potempa9Juhi Bagaitkar10Center for Microbe and Immunity Research, Nationwide Children’s HospitalDepartment of Pathology and Immunology, Washington University School of Medicine in St. LouisDepartment of Oral Immunology and Infectious Diseases, University of LouisvilleDepartment of Physiology & Pharmacology, Cumming School of Medicine, University of CalgaryDepartment of Physiology & Pharmacology, Cumming School of Medicine, University of CalgaryDepartment of Physiology & Pharmacology, Cumming School of Medicine, University of CalgaryDepartment of Physiology & Pharmacology, Cumming School of Medicine, University of CalgaryDepartment of Oral Immunology and Infectious Diseases, University of LouisvilleDepartment of Pathology and Immunology, Washington University School of Medicine in St. LouisDepartment of Oral Immunology and Infectious Diseases, University of LouisvilleCenter for Microbe and Immunity Research, Nationwide Children’s HospitalAbstract Neutrophils are highly abundant in the oral mucosal tissues, and their balanced activation and clearance are essential for immune homeostasis. Here, we demonstrate that neutrophils infected with the bacterial pathogen Porphyromonas gingivalis (Pg) are captured alive by macrophages in a manner that bypasses all known receptor-ligand interactions involved in the phagocytosis of either live or dead cells. Mechanistically, upon interaction with Pg, or its protease RgpB (gingipains), live neutrophils undergo rapid remodeling of their proteomes, generating neoepitopes. N-terminomics-based proteomic profiling identified multiple RgpB cleavage sites on several azurophilic granule proteins that are translocated to the surface of live neutrophils via low-level degranulation and activate macrophage αMβ2 integrin receptors, thus mediating internalization of non-apoptotic neutrophils within macrophage phagosomes. Macrophages with entrapped live neutrophils exhibit phenotypic and transcriptional reprogramming, consistent with inflammatory outcomes in vitro and in vivo. In contrast to the immunosuppressive outcomes associated with efferocytosis of apoptotic neutrophils, live neutrophil entrapment failed to fully activate several catabolic and metabolic processes and exhibited a defective activation of PPAR-γ mediated pro-resolution pathways, thereby promoting bacterial persistence and hindering the resolution of inflammation. Thus, our data demonstrate a novel immune subversion strategy unique to Pg and reveal a previously unknown mode of live neutrophil sequestration into macrophages during an infection.https://doi.org/10.1038/s41419-025-07808-5 |
| spellingShingle | Kelley N. Cooper Marina Terekhova Barbara Potempa Ana D’Aubeterre Jerome Timbol Si An Chen Antoine Dufour Shunying Jin Maxim N. Artyomov Jan Potempa Juhi Bagaitkar The trapping of live neutrophils by macrophages during infection Cell Death and Disease |
| title | The trapping of live neutrophils by macrophages during infection |
| title_full | The trapping of live neutrophils by macrophages during infection |
| title_fullStr | The trapping of live neutrophils by macrophages during infection |
| title_full_unstemmed | The trapping of live neutrophils by macrophages during infection |
| title_short | The trapping of live neutrophils by macrophages during infection |
| title_sort | trapping of live neutrophils by macrophages during infection |
| url | https://doi.org/10.1038/s41419-025-07808-5 |
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