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Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation

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...

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Autores principales: Morita, Yugo, Saito, Motoo, Rangel-Moreno, Javier, Franchini, Anthony M., Owen, John R., Martinez, John C., Daiss, John L., de Mesy Bentley, Karen L., Kates, Stephen L., Schwarz, Edward M., Muthukrishnan, Gowrishankar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9418173/
https://www.ncbi.nlm.nih.gov/pubmed/36028492
http://dx.doi.org/10.1038/s41413-022-00228-7
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author Morita, Yugo
Saito, Motoo
Rangel-Moreno, Javier
Franchini, Anthony M.
Owen, John R.
Martinez, John C.
Daiss, John L.
de Mesy Bentley, Karen L.
Kates, Stephen L.
Schwarz, Edward M.
Muthukrishnan, Gowrishankar
author_facet Morita, Yugo
Saito, Motoo
Rangel-Moreno, Javier
Franchini, Anthony M.
Owen, John R.
Martinez, John C.
Daiss, John L.
de Mesy Bentley, Karen L.
Kates, Stephen L.
Schwarz, Edward M.
Muthukrishnan, Gowrishankar
author_sort Morita, Yugo
collection PubMed
description 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.
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spelling pubmed-94181732022-08-28 Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation Morita, Yugo Saito, Motoo Rangel-Moreno, Javier Franchini, Anthony M. Owen, John R. Martinez, John C. Daiss, John L. de Mesy Bentley, Karen L. Kates, Stephen L. Schwarz, Edward M. Muthukrishnan, Gowrishankar Bone Res Article 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. Nature Publishing Group UK 2022-08-26 /pmc/articles/PMC9418173/ /pubmed/36028492 http://dx.doi.org/10.1038/s41413-022-00228-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Morita, Yugo
Saito, Motoo
Rangel-Moreno, Javier
Franchini, Anthony M.
Owen, John R.
Martinez, John C.
Daiss, John L.
de Mesy Bentley, Karen L.
Kates, Stephen L.
Schwarz, Edward M.
Muthukrishnan, Gowrishankar
Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation
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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9418173/
https://www.ncbi.nlm.nih.gov/pubmed/36028492
http://dx.doi.org/10.1038/s41413-022-00228-7
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