Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation
Abstract Interleukin-27 is a pleiotropic cytokine whose functions during bacterial infections remain controversial, and its role in patients with S. aureus osteomyelitis is unknown. To address this knowledge gap, we completed a clinical study and observed elevated serum IL-27 levels (20-fold higher,...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-08-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-022-00228-7 |
| _version_ | 1828258301400317952 |
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| author | Yugo Morita Motoo Saito Javier Rangel-Moreno Anthony M. Franchini John R. Owen John C. Martinez John L. Daiss Karen L. de Mesy Bentley Stephen L. Kates Edward M. Schwarz Gowrishankar Muthukrishnan |
| author_facet | Yugo Morita Motoo Saito Javier Rangel-Moreno Anthony M. Franchini John R. Owen John C. Martinez John L. Daiss Karen L. de Mesy Bentley Stephen L. Kates Edward M. Schwarz Gowrishankar Muthukrishnan |
| author_sort | Yugo Morita |
| collection | DOAJ |
| description | Abstract Interleukin-27 is a pleiotropic cytokine whose functions during bacterial infections remain controversial, and its role in patients with S. aureus osteomyelitis is unknown. To address this knowledge gap, we completed a clinical study and observed elevated serum IL-27 levels (20-fold higher, P < 0.05) in patients compared with healthy controls. Remarkably, IL-27 serum levels were 60-fold higher in patients immediately following septic death than in uninfected patients (P < 0.05), suggesting a pathogenic role of IL-27. To test this hypothesis, we evaluated S. aureus osteomyelitis in WT and IL-27Rα−/− mice with and without exogenous IL-27 induction by intramuscular injection of rAAV-IL-27p28 or rAAV-GFP, respectively. We found that IL-27 was induced at the surgical site within 1 day of S. aureus infection of bone and was expressed by M0, M1 and M2 macrophages and osteoblasts but not by osteoclasts. Unexpectedly, exogenous IL-27p28 (~2 ng·mL−1 in serum) delivery ameliorated soft tissue abscesses and peri-implant bone loss during infection, accompanied by enhanced local IL-27 expression, significant accumulation of RORγt+ neutrophils at the infection site, a decrease in RANK+ cells, and compromised osteoclast formation. These effects were not observed in IL-27Rα−/− mice compared with WT mice, suggesting that IL-27 is dispensable for immunity but mediates redundant immune and bone cell functions during infection. In vitro studies and bulk RNA-seq of infected tibiae showed that IL-27 increased nos1, nos2, il17a, il17f, and rorc expression but did not directly stimulate chemotaxis. Collectively, these results identify a novel phenomenon of IL-27 expression by osteoblasts immediately following S. aureus infection of bone and suggest a protective role of systemic IL-27 in osteomyelitis. |
| first_indexed | 2024-04-13T02:52:00Z |
| format | Article |
| id | doaj.art-225a91035f104c71992dd36009af973e |
| institution | Directory Open Access Journal |
| issn | 2095-6231 |
| language | English |
| last_indexed | 2024-04-13T02:52:00Z |
| publishDate | 2022-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj.art-225a91035f104c71992dd36009af973e2022-12-22T03:05:49ZengNature Publishing GroupBone Research2095-62312022-08-0110111210.1038/s41413-022-00228-7Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activationYugo Morita0Motoo Saito1Javier Rangel-Moreno2Anthony M. Franchini3John R. Owen4John C. Martinez5John L. Daiss6Karen L. de Mesy Bentley7Stephen L. Kates8Edward M. Schwarz9Gowrishankar Muthukrishnan10Center for Musculoskeletal Research, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical CenterDivision of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical CenterDepartment of Environmental Medicine, University of Rochester School of Medicine and DentistryDepartment of Orthopedic Surgery, Virginia Commonwealth UniversityCenter for Musculoskeletal Research, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical CenterDepartment of Orthopedic Surgery, Virginia Commonwealth UniversityCenter for Musculoskeletal Research, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical CenterAbstract Interleukin-27 is a pleiotropic cytokine whose functions during bacterial infections remain controversial, and its role in patients with S. aureus osteomyelitis is unknown. To address this knowledge gap, we completed a clinical study and observed elevated serum IL-27 levels (20-fold higher, P < 0.05) in patients compared with healthy controls. Remarkably, IL-27 serum levels were 60-fold higher in patients immediately following septic death than in uninfected patients (P < 0.05), suggesting a pathogenic role of IL-27. To test this hypothesis, we evaluated S. aureus osteomyelitis in WT and IL-27Rα−/− mice with and without exogenous IL-27 induction by intramuscular injection of rAAV-IL-27p28 or rAAV-GFP, respectively. We found that IL-27 was induced at the surgical site within 1 day of S. aureus infection of bone and was expressed by M0, M1 and M2 macrophages and osteoblasts but not by osteoclasts. Unexpectedly, exogenous IL-27p28 (~2 ng·mL−1 in serum) delivery ameliorated soft tissue abscesses and peri-implant bone loss during infection, accompanied by enhanced local IL-27 expression, significant accumulation of RORγt+ neutrophils at the infection site, a decrease in RANK+ cells, and compromised osteoclast formation. These effects were not observed in IL-27Rα−/− mice compared with WT mice, suggesting that IL-27 is dispensable for immunity but mediates redundant immune and bone cell functions during infection. In vitro studies and bulk RNA-seq of infected tibiae showed that IL-27 increased nos1, nos2, il17a, il17f, and rorc expression but did not directly stimulate chemotaxis. Collectively, these results identify a novel phenomenon of IL-27 expression by osteoblasts immediately following S. aureus infection of bone and suggest a protective role of systemic IL-27 in osteomyelitis.https://doi.org/10.1038/s41413-022-00228-7 |
| spellingShingle | Yugo Morita Motoo Saito Javier Rangel-Moreno Anthony M. Franchini John R. Owen John C. Martinez John L. Daiss Karen L. de Mesy Bentley Stephen L. Kates Edward M. Schwarz Gowrishankar Muthukrishnan Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation Bone Research |
| title | Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation |
| title_full | Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation |
| title_fullStr | Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation |
| title_full_unstemmed | Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation |
| title_short | Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation |
| title_sort | systemic il 27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation |
| url | https://doi.org/10.1038/s41413-022-00228-7 |
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