دورية أكاديمية
Neutrophil and NETosis Modulation in Traumatic Heterotopic Ossification.
العنوان: | Neutrophil and NETosis Modulation in Traumatic Heterotopic Ossification. |
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المؤلفون: | Nunez JH; Department of Surgery, Center for Organogenesis and Trauma, University of Texas, Southwestern, Dallas, TX., Juan C; Department of Surgery, Center for Organogenesis and Trauma, University of Texas, Southwestern, Dallas, TX., Sun Y; Department of Surgery, Center for Organogenesis and Trauma, University of Texas, Southwestern, Dallas, TX., Hong J; Department of Surgery, Center for Organogenesis and Trauma, University of Texas, Southwestern, Dallas, TX., Bancroft AC; Department of Surgery, Center for Organogenesis and Trauma, University of Texas, Southwestern, Dallas, TX., Hwang C; Department of Plastic Surgery, Harvard University, Cambridge, MA., Medrano JM; Department of Surgery, Center for Organogenesis and Trauma, University of Texas, Southwestern, Dallas, TX., Huber AK; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI., Tower RJ; Department of Surgery, Center for Organogenesis and Trauma, University of Texas, Southwestern, Dallas, TX., Levi B; Department of Surgery, Center for Organogenesis and Trauma, University of Texas, Southwestern, Dallas, TX. |
المصدر: | Annals of surgery [Ann Surg] 2023 Dec 01; Vol. 278 (6), pp. e1289-e1298. Date of Electronic Publication: 2023 Jun 16. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
اللغة: | English |
بيانات الدورية: | Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0372354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-1140 (Electronic) Linking ISSN: 00034932 NLM ISO Abbreviation: Ann Surg Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Philadelphia, PA : Lippincott Williams & Wilkins |
مواضيع طبية MeSH: | Neutrophils*/metabolism , Extracellular Traps*/metabolism, Animals ; Mice ; Hydroxychloroquine/metabolism ; Immunity, Innate ; DNA/metabolism |
مستخلص: | Objective: To characterize the role of neutrophil extracellular traps (NETs) in heterotopic ossification (HO) formation and progression and to use mechanical and pharmacological methods to decrease NETosis and mitigate HO formation. Background: Traumatic HO is the aberrant osteochondral differentiation of mesenchymal progenitor cells after traumatic injury, burns, or surgery. While the innate immune response has been shown to be necessary for HO formation, the specific immune cell phenotype and function remain unknown. Neutrophils, one of the earliest immune cells to respond after HO-inducing injuries, can extrude DNA, forming highly inflammatory NETs. We hypothesized that neutrophils and NETs would be diagnostic biomarkers and therapeutic targets for the detection and mitigation of HO. Methods: C57BL6J mice underwent burn/tenotomy (a well-established mouse model of HO) or a non-HO-forming sham injury. These mice were either (1) ambulated ad libitum, (2) ambulated ad libitum with daily intraperitoneal hydroxychloroquine, ODN-2088 (both known to affect NETosis pathways), or control injections, or (3) had the injured hind limb immobilized. Single-cell analysis was performed to analyze neutrophils, NETosis, and downstream signaling after the HO-forming injury. Immunofluorescence microscopy was used to visualize NETosis at the HO site and neutrophils were identified using flow cytometry. Serum and cell lysates from HO sites were analyzed using enzyme-linked immunosorbent assay for myeloperoxidase-DNA and ELA2-DNA complexes to identify NETosis. Micro-computerized tomography was performed on all groups to analyze the HO volume. Results: Molecular and transcriptional analyses revealed the presence of NETs within the HO injury site, which peaked in the early phases after injury. These NETs were highly restricted to the HO site, with gene signatures derived from both in vitro NET induction and clinical neutrophil characterizations showing a high degree of NET "priming" at the site of injury, but not in neutrophils in the blood or bone marrow. Cell-cell communication analyses revealed that this localized NET formation coincided with high levels of toll-like receptor signaling specific to neutrophils at the injury site. Reducing the overall neutrophil abundance within the injury site, either pharmacologically through treatment with hydroxychloroquine, the toll-like receptor 9 inhibitor OPN-2088, or mechanical treatment with limb offloading, results in the mitigation of HO formation. Conclusions: These data provide a further understanding of the ability of neutrophils to form NETs at the injury site, clarify the role of neutrophils in HO, and identify potential diagnostic and therapeutic targets for HO mitigation. Competing Interests: The authors report no conflicts of interest. (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.) |
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معلومات مُعتمدة: | R61 AR078072 United States AR NIAMS NIH HHS |
المشرفين على المادة: | 4QWG6N8QKH (Hydroxychloroquine) 9007-49-2 (DNA) |
تواريخ الأحداث: | Date Created: 20230616 Date Completed: 20231109 Latest Revision: 20240218 |
رمز التحديث: | 20240218 |
مُعرف محوري في PubMed: | PMC10724380 |
DOI: | 10.1097/SLA.0000000000005940 |
PMID: | 37325925 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1528-1140 |
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DOI: | 10.1097/SLA.0000000000005940 |