Extracellular vimentin is a damage-associated molecular pattern protein serving as an agonist of TLR4 in human neutrophils
Abstract Background Vimentin is a type III intermediate filament protein that plays an important role in cytoskeletal mechanics. It is now known that vimentin also has distinct functions outside the cell. Recent studies show the controlled release of vimentin into the extracellular environment, wher...
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BMC
2025-02-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02062-w |
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| author | Łukasz Suprewicz Krzysztof Fiedoruk Karol Skłodowski Evan Hutt Magdalena Zakrzewska Alicja Walewska Piotr Deptuła Agata Lesiak Sławomir Okła Peter A. Galie Alison E. Patteson Paul A. Janmey Robert Bucki |
| author_facet | Łukasz Suprewicz Krzysztof Fiedoruk Karol Skłodowski Evan Hutt Magdalena Zakrzewska Alicja Walewska Piotr Deptuła Agata Lesiak Sławomir Okła Peter A. Galie Alison E. Patteson Paul A. Janmey Robert Bucki |
| author_sort | Łukasz Suprewicz |
| collection | DOAJ |
| description | Abstract Background Vimentin is a type III intermediate filament protein that plays an important role in cytoskeletal mechanics. It is now known that vimentin also has distinct functions outside the cell. Recent studies show the controlled release of vimentin into the extracellular environment, where it functions as a signaling molecule. Such observations are expanding our current knowledge of vimentin as a structural cellular component towards additional roles as an active participant in cell signaling. Methods Our study investigates the immunological roles of extracellular vimentin (eVim) and its citrullinated form (CitVim) as a damage-associated molecular pattern (DAMP) engaging the Toll-like receptor 4 (TLR4) of human neutrophils. We used in vitro assays to study neutrophil migration through endothelial cell monolayers and activation markers such as NADPH oxidase subunit 2 (NOX2/gp91phox). The comparison of eVim with CitVim and its effect on human neutrophils was extended to the induction of extracellular traps (NETs) and phagocytosis of pathogens. Results Both eVim and CitVim interact with and trigger TLR4, leading to increased neutrophil migration and adhesion. CitVim stimulated the enhanced migratory ability of neutrophils, activation of NF-κB, and induction of NET formation mainly mediated through reactive oxygen species (ROS)-dependent and TLR4-dependent pathways. In contrast, neutrophils exposed to non-citrullinated vimentin exhibited higher efficiency in favoring pathogen phagocytosis, such as Escherichia coli and Candida albicans, compared to CitVim. Conclusions Our study identifies new functions of eVim in its native and modified forms as an extracellular matrix DAMP and highlights its importance in the modulation of immune system functions. The differential effects of eVim and CitVim on neutrophil functions highlight their potential as new molecular targets for therapeutic strategies aimed at regulation of neutrophil activity in different pathological conditions. This, in turn, opens new windows of therapeutic intervention in inflammatory and immunological diseases characterized by immune system dysfunction, in which eVim and CitVim play a key role. |
| format | Article |
| id | doaj-art-76b5dc58d30e4571a9d89c3b94a16b69 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-76b5dc58d30e4571a9d89c3b94a16b692025-02-09T12:47:26ZengBMCCell Communication and Signaling1478-811X2025-02-0123112210.1186/s12964-025-02062-wExtracellular vimentin is a damage-associated molecular pattern protein serving as an agonist of TLR4 in human neutrophilsŁukasz Suprewicz0Krzysztof Fiedoruk1Karol Skłodowski2Evan Hutt3Magdalena Zakrzewska4Alicja Walewska5Piotr Deptuła6Agata Lesiak7Sławomir Okła8Peter A. Galie9Alison E. Patteson10Paul A. Janmey11Robert Bucki12Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of BialystokDepartment of Medical Microbiology and Nanobiomedical Engineering, Medical University of BialystokDepartment of Medical Microbiology and Nanobiomedical Engineering, Medical University of BialystokDepartment of Biomedical Engineering, Rowan UniversityDepartment of Medical Microbiology and Nanobiomedical Engineering, Medical University of BialystokCentre of Regenerative Medicine, Medical University of BialystokIndependent Laboratory of Nanomedicine, Medical University of BialystokInstitute of Medical Sciences, Collegium Medicum, Jan Kochanowski University of KielceInstitute of Medical Sciences, Collegium Medicum, Jan Kochanowski University of KielceDepartment of Biomedical Engineering, Rowan UniversityPhysics Department and BioInspired Institute, Syracuse UniversityDepartment of Physiology and Institute for Medicine and Engineering, University of PennsylvaniaDepartment of Medical Microbiology and Nanobiomedical Engineering, Medical University of BialystokAbstract Background Vimentin is a type III intermediate filament protein that plays an important role in cytoskeletal mechanics. It is now known that vimentin also has distinct functions outside the cell. Recent studies show the controlled release of vimentin into the extracellular environment, where it functions as a signaling molecule. Such observations are expanding our current knowledge of vimentin as a structural cellular component towards additional roles as an active participant in cell signaling. Methods Our study investigates the immunological roles of extracellular vimentin (eVim) and its citrullinated form (CitVim) as a damage-associated molecular pattern (DAMP) engaging the Toll-like receptor 4 (TLR4) of human neutrophils. We used in vitro assays to study neutrophil migration through endothelial cell monolayers and activation markers such as NADPH oxidase subunit 2 (NOX2/gp91phox). The comparison of eVim with CitVim and its effect on human neutrophils was extended to the induction of extracellular traps (NETs) and phagocytosis of pathogens. Results Both eVim and CitVim interact with and trigger TLR4, leading to increased neutrophil migration and adhesion. CitVim stimulated the enhanced migratory ability of neutrophils, activation of NF-κB, and induction of NET formation mainly mediated through reactive oxygen species (ROS)-dependent and TLR4-dependent pathways. In contrast, neutrophils exposed to non-citrullinated vimentin exhibited higher efficiency in favoring pathogen phagocytosis, such as Escherichia coli and Candida albicans, compared to CitVim. Conclusions Our study identifies new functions of eVim in its native and modified forms as an extracellular matrix DAMP and highlights its importance in the modulation of immune system functions. The differential effects of eVim and CitVim on neutrophil functions highlight their potential as new molecular targets for therapeutic strategies aimed at regulation of neutrophil activity in different pathological conditions. This, in turn, opens new windows of therapeutic intervention in inflammatory and immunological diseases characterized by immune system dysfunction, in which eVim and CitVim play a key role.https://doi.org/10.1186/s12964-025-02062-wNeutrophilsExtracellular vimentinCitrullinated vimentinInflammationToll-like receptor 4 |
| spellingShingle | Łukasz Suprewicz Krzysztof Fiedoruk Karol Skłodowski Evan Hutt Magdalena Zakrzewska Alicja Walewska Piotr Deptuła Agata Lesiak Sławomir Okła Peter A. Galie Alison E. Patteson Paul A. Janmey Robert Bucki Extracellular vimentin is a damage-associated molecular pattern protein serving as an agonist of TLR4 in human neutrophils Cell Communication and Signaling Neutrophils Extracellular vimentin Citrullinated vimentin Inflammation Toll-like receptor 4 |
| title | Extracellular vimentin is a damage-associated molecular pattern protein serving as an agonist of TLR4 in human neutrophils |
| title_full | Extracellular vimentin is a damage-associated molecular pattern protein serving as an agonist of TLR4 in human neutrophils |
| title_fullStr | Extracellular vimentin is a damage-associated molecular pattern protein serving as an agonist of TLR4 in human neutrophils |
| title_full_unstemmed | Extracellular vimentin is a damage-associated molecular pattern protein serving as an agonist of TLR4 in human neutrophils |
| title_short | Extracellular vimentin is a damage-associated molecular pattern protein serving as an agonist of TLR4 in human neutrophils |
| title_sort | extracellular vimentin is a damage associated molecular pattern protein serving as an agonist of tlr4 in human neutrophils |
| topic | Neutrophils Extracellular vimentin Citrullinated vimentin Inflammation Toll-like receptor 4 |
| url | https://doi.org/10.1186/s12964-025-02062-w |
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