Itaconate-producing neutrophils regulate local and systemic inflammation following trauma
Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries that undergo normal and aberrant repair were evaluated by m...
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| Published in | JCI insight Vol. 8; no. 20 |
|---|---|
| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Society for Clinical Investigation
23.10.2023
American Society for Clinical investigation |
| Subjects | |
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| Abstract | Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries that undergo normal and aberrant repair were evaluated by metabolic profiling to determine its impact on healing outcomes. Metabolomics revealed an increasing abundance of the immunomodulatory metabolite itaconate within the injury site. Subsequent single-cell RNA-Seq and molecular and metabolomic validation identified a highly mature neutrophil subtype, not macrophages, as the primary producers of itaconate following trauma. These mature itaconate-producing neutrophils were highly inflammatory, producing cytokines that promote local injury fibrosis before cycling back to the bone marrow. In the bone marrow, itaconate was shown to alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby regulating systemic inflammation. Therapeutically, exogenous itaconate was found to reduce injury-site inflammation, promoting tenogenic differentiation and impairing aberrant vascularization with disease-ameliorating effects. These results present an intriguing role for cycling neutrophils as a sensor of inflammation induced by injury - potentially regulating immune cell production in the bone marrow through delivery of endogenously produced itaconate - and demonstrate a therapeutic potential for exogenous itaconate following tendon injury. |
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| AbstractList | Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries that undergo normal and aberrant repair were evaluated by metabolic profiling to determine its impact on healing outcomes. Metabolomics revealed an increasing abundance of the immunomodulatory metabolite itaconate within the injury site. Subsequent single-cell RNA-Seq and molecular and metabolomic validation identified a highly mature neutrophil subtype, not macrophages, as the primary producers of itaconate following trauma. These mature itaconate-producing neutrophils were highly inflammatory, producing cytokines that promote local injury fibrosis before cycling back to the bone marrow. In the bone marrow, itaconate was shown to alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby regulating systemic inflammation. Therapeutically, exogenous itaconate was found to reduce injury-site inflammation, promoting tenogenic differentiation and impairing aberrant vascularization with disease-ameliorating effects. These results present an intriguing role for cycling neutrophils as a sensor of inflammation induced by injury — potentially regulating immune cell production in the bone marrow through delivery of endogenously produced itaconate — and demonstrate a therapeutic potential for exogenous itaconate following tendon injury Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries which undergo normal and aberrant repair were evaluated by metabolic profiling to determine its impact on healing outcomes. Metabolomics revealed an increasing abundance of the immunomodulatory metabolite itaconate with the injury site. Subsequent single-cell RNA sequencing, molecular and metabolomic validation identified a highly mature neutrophil subtype, not macrophages, as the primary producers of itaconate following trauma. These mature itaconate-producing neutrophils were highly inflammatory, producing cytokines that promote local injury fibrosis before cycling back to the bone marrow. In the bone marrow, itaconate was shown to alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby regulating systemic inflammation. Therapeutically, exogenous itaconate was found to reduce injury site inflammation, promoting tenogenic differentiation and impairing aberrant vascularization with disease ameliorating effects. These results present an intriguing role for cycling neutrophils as a sensor of inflammation induced by injury, potentially regulating immune cell production in the bone marrow, through delivery of endogenously produced itaconate and demonstrate a therapeutic potential for exogenous itaconate following tendon injury.Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries which undergo normal and aberrant repair were evaluated by metabolic profiling to determine its impact on healing outcomes. Metabolomics revealed an increasing abundance of the immunomodulatory metabolite itaconate with the injury site. Subsequent single-cell RNA sequencing, molecular and metabolomic validation identified a highly mature neutrophil subtype, not macrophages, as the primary producers of itaconate following trauma. These mature itaconate-producing neutrophils were highly inflammatory, producing cytokines that promote local injury fibrosis before cycling back to the bone marrow. In the bone marrow, itaconate was shown to alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby regulating systemic inflammation. Therapeutically, exogenous itaconate was found to reduce injury site inflammation, promoting tenogenic differentiation and impairing aberrant vascularization with disease ameliorating effects. These results present an intriguing role for cycling neutrophils as a sensor of inflammation induced by injury, potentially regulating immune cell production in the bone marrow, through delivery of endogenously produced itaconate and demonstrate a therapeutic potential for exogenous itaconate following tendon injury. Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries that undergo normal and aberrant repair were evaluated by metabolic profiling to determine its impact on healing outcomes. Metabolomics revealed an increasing abundance of the immunomodulatory metabolite itaconate within the injury site. Subsequent single-cell RNA-Seq and molecular and metabolomic validation identified a highly mature neutrophil subtype, not macrophages, as the primary producers of itaconate following trauma. These mature itaconate-producing neutrophils were highly inflammatory, producing cytokines that promote local injury fibrosis before cycling back to the bone marrow. In the bone marrow, itaconate was shown to alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby regulating systemic inflammation. Therapeutically, exogenous itaconate was found to reduce injury-site inflammation, promoting tenogenic differentiation and impairing aberrant vascularization with disease-ameliorating effects. These results present an intriguing role for cycling neutrophils as a sensor of inflammation induced by injury - potentially regulating immune cell production in the bone marrow through delivery of endogenously produced itaconate - and demonstrate a therapeutic potential for exogenous itaconate following tendon injury. |
| Author | Ostashevskaya-Gohstand, Sonya Vishlaghi, Neda Hook, Jessica S Moreland, Jessica G Xu, Lin Crossley, Janna L Guo, Lei Tower, Robert J Juan, Conan Horswill, Alexander R Levi, Benjamin Hoxhaj, Gerta Comazzetto, Stefano |
| AuthorAffiliation | 1 Department of Surgery 3 Department of Pediatrics, and 4 Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, Texas, USA 2 Children’s Research Institute and Department of Pediatrics 5 Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA |
| AuthorAffiliation_xml | – name: 4 Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, Texas, USA – name: 1 Department of Surgery – name: 2 Children’s Research Institute and Department of Pediatrics – name: 3 Department of Pediatrics, and – name: 5 Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA |
| Author_xml | – sequence: 1 givenname: Janna L surname: Crossley fullname: Crossley, Janna L organization: Department of Surgery – sequence: 2 givenname: Sonya surname: Ostashevskaya-Gohstand fullname: Ostashevskaya-Gohstand, Sonya organization: Department of Surgery – sequence: 3 givenname: Stefano surname: Comazzetto fullname: Comazzetto, Stefano organization: Children's Research Institute and Department of Pediatrics – sequence: 4 givenname: Jessica S surname: Hook fullname: Hook, Jessica S organization: Department of Pediatrics, and – sequence: 5 givenname: Lei surname: Guo fullname: Guo, Lei organization: Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, Texas, USA – sequence: 6 givenname: Neda surname: Vishlaghi fullname: Vishlaghi, Neda organization: Department of Surgery – sequence: 7 givenname: Conan surname: Juan fullname: Juan, Conan organization: Department of Surgery – sequence: 8 givenname: Lin surname: Xu fullname: Xu, Lin organization: Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, Texas, USA – sequence: 9 givenname: Alexander R surname: Horswill fullname: Horswill, Alexander R organization: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA – sequence: 10 givenname: Gerta surname: Hoxhaj fullname: Hoxhaj, Gerta organization: Children's Research Institute and Department of Pediatrics – sequence: 11 givenname: Jessica G surname: Moreland fullname: Moreland, Jessica G organization: Department of Pediatrics, and – sequence: 12 givenname: Robert J surname: Tower fullname: Tower, Robert J organization: Department of Surgery – sequence: 13 givenname: Benjamin surname: Levi fullname: Levi, Benjamin organization: Department of Surgery |
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| CitedBy_id | crossref_primary_10_1038_s44324_024_00008_3 crossref_primary_10_1016_j_freeradbiomed_2024_04_218 crossref_primary_10_1089_wound_2023_0149 crossref_primary_10_1016_j_tem_2024_02_004 crossref_primary_10_3389_fimmu_2024_1352165 crossref_primary_10_1038_s12276_024_01270_7 crossref_primary_10_1093_jleuko_qiae057 crossref_primary_10_1016_j_celrep_2024_114049 |
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| Title | Itaconate-producing neutrophils regulate local and systemic inflammation following trauma |
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