HMGB1-C1q complexes regulate macrophage function by switching between leukotriene and specialized proresolving mediator biosynthesis
Macrophage polarization is critical to inflammation and resolution of inflammation. We previously showed that high-mobility group box 1 (HMGB1) can engage receptor for advanced glycation end product (RAGE) to direct monocytes to a proinflammatory phenotype characterized by production of type 1 IFN and proinflammatory cytokines. In contrast, HMGB1 plus C1q form a tetramolecular complex cross-linking RAGE and LAIR-1 and directing monocytes to an antiinflammatory phenotype. Lipid mediators, as well as cytokines, help establish a milieu favoring either inflammation or resolution of inflammation. This study focuses on the induction of lipid mediators by HMGB1 and HMGB1 plus C1q and their regulation of IRF5, a transcription factor critical for the induction and maintenance of proinflammatory macrophages. Here, we show that HMGB1 induces leukotriene production through a RAGE-dependent pathway, while HMGB1 plus C1q induces specialized proresolving lipid mediators lipoxin A4, resolvin D1, and resolvin D2 through a RAGE- and LAIR-1-dependent pathway. Leukotriene exposure contributes to induction of IRF5 in a positive-feedback loop. In contrast, resolvins (at 20 nM) block IRF5 induction and prevent the differentiation of inflammatory macrophages. Finally, we have generated a molecular mimic of HMGB1 plus C1q, which cross-links RAGE and LAIR-1 and polarizes monocytes to an antiinflammatory phenotype. These findings may provide a mechanism to control nonresolving inflammation in many pathologic conditions.
| Errataetall: |
CommentIn: Proc Natl Acad Sci U S A. 2019 Nov 12;116(46):22901-22903. - PMID 31653759 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:116 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 116(2019), 46 vom: 12. Nov., Seite 23254-23263 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Tianye [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.04.2020 Date Revised 01.04.2020 published: Print-Electronic CommentIn: Proc Natl Acad Sci U S A. 2019 Nov 12;116(46):22901-22903. - PMID 31653759 Citation Status MEDLINE |
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| doi: |
10.1073/pnas.1907490116 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM301780986 |
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| 500 | |a Date Completed 01.04.2020 | ||
| 500 | |a Date Revised 01.04.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Proc Natl Acad Sci U S A. 2019 Nov 12;116(46):22901-22903. - PMID 31653759 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Macrophage polarization is critical to inflammation and resolution of inflammation. We previously showed that high-mobility group box 1 (HMGB1) can engage receptor for advanced glycation end product (RAGE) to direct monocytes to a proinflammatory phenotype characterized by production of type 1 IFN and proinflammatory cytokines. In contrast, HMGB1 plus C1q form a tetramolecular complex cross-linking RAGE and LAIR-1 and directing monocytes to an antiinflammatory phenotype. Lipid mediators, as well as cytokines, help establish a milieu favoring either inflammation or resolution of inflammation. This study focuses on the induction of lipid mediators by HMGB1 and HMGB1 plus C1q and their regulation of IRF5, a transcription factor critical for the induction and maintenance of proinflammatory macrophages. Here, we show that HMGB1 induces leukotriene production through a RAGE-dependent pathway, while HMGB1 plus C1q induces specialized proresolving lipid mediators lipoxin A4, resolvin D1, and resolvin D2 through a RAGE- and LAIR-1-dependent pathway. Leukotriene exposure contributes to induction of IRF5 in a positive-feedback loop. In contrast, resolvins (at 20 nM) block IRF5 induction and prevent the differentiation of inflammatory macrophages. Finally, we have generated a molecular mimic of HMGB1 plus C1q, which cross-links RAGE and LAIR-1 and polarizes monocytes to an antiinflammatory phenotype. These findings may provide a mechanism to control nonresolving inflammation in many pathologic conditions | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a C1q | |
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| 650 | 4 | |a SPMs | |
| 650 | 4 | |a leukotriene | |
| 650 | 7 | |a Ager protein, mouse |2 NLM | |
| 650 | 7 | |a HMGB1 Protein |2 NLM | |
| 650 | 7 | |a HMGB1 protein, mouse |2 NLM | |
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| 650 | 7 | |a Receptor for Advanced Glycation End Products |2 NLM | |
| 650 | 7 | |a Receptors, Immunologic |2 NLM | |
| 650 | 7 | |a leukocyte-associated immunoglobulin-like receptor 1 |2 NLM | |
| 650 | 7 | |a Leukotriene B4 |2 NLM | |
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| 650 | 7 | |a Complement C1q |2 NLM | |
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| 650 | 7 | |a Arachidonate 5-Lipoxygenase |2 NLM | |
| 650 | 7 | |a EC 1.13.11.34 |2 NLM | |
| 700 | 1 | |a Xiang, Alec |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Travis |e verfasserin |4 aut | |
| 700 | 1 | |a Doran, Amanda C |e verfasserin |4 aut | |
| 700 | 1 | |a Tracey, Kevin J |e verfasserin |4 aut | |
| 700 | 1 | |a Barnes, Betsy J |e verfasserin |4 aut | |
| 700 | 1 | |a Tabas, Ira |e verfasserin |4 aut | |
| 700 | 1 | |a Son, Myoungsun |e verfasserin |4 aut | |
| 700 | 1 | |a Diamond, Betty |e verfasserin |4 aut | |
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