Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes
C5a is an inflammatory mediator generated by complement activation that positively regulates various arms of immune defense, including Toll-like receptor 4 (TLR4) signaling. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is activated by pathogen products and cellular/ti...
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| Format: | Article |
| Language: | English |
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Wiley
2016-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2016/1340156 |
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| author | Mikel D. Haggadone Jamison J. Grailer Fatemeh Fattahi Firas S. Zetoune Peter A. Ward |
| author_facet | Mikel D. Haggadone Jamison J. Grailer Fatemeh Fattahi Firas S. Zetoune Peter A. Ward |
| author_sort | Mikel D. Haggadone |
| collection | DOAJ |
| description | C5a is an inflammatory mediator generated by complement activation that positively regulates various arms of immune defense, including Toll-like receptor 4 (TLR4) signaling. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is activated by pathogen products and cellular/tissue damage products and is a major contributor of IL-1β. In this study, we investigate whether C5a modulates lipopolysaccharide- (LPS-) induced NLRP3 inflammasome activation in myeloid cells. Appearance of plasma IL-1β during endotoxemia was reduced in C5aR1-/- mice when compared to wild-type mice. In vitro, C5a significantly enhanced LPS-induced production of IL-1β in bone marrow Ly6C-high inflammatory monocytes, accompanied by augmented intracellular pro-IL-1β expression. This effect was abolished during p38 blockade by SB 203580 and in the absence of C5aR1. Conversely, C5a suppressed LPS-induced macrophage production of IL-1β, which was accompanied by attenuated levels of pro-IL-1β, NLRP3, and caspase-1 expression. C5a’s suppressive effects were negated during phosphoinositide 3-kinase (PI3K) inhibition by wortmannin but were largely preserved in the absence of C5aR1. Thus, C5a bidirectionally amplifies TLR4-mediated NLRP3 inflammasome activation in monocytes while suppressing this pathway in macrophages. However, as C5aR1 deficiency attenuates the IL-1β response to LPS challenge in vivo, our results suggest overall that C5a augments physiologic inflammasome responses. |
| format | Article |
| id | doaj-art-e4c0e1b6c09a48a9a8e748c783320fdd |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-e4c0e1b6c09a48a9a8e748c783320fdd2025-08-20T03:26:26ZengWileyMediators of Inflammation0962-93511466-18612016-01-01201610.1155/2016/13401561340156Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and MonocytesMikel D. Haggadone0Jamison J. Grailer1Fatemeh Fattahi2Firas S. Zetoune3Peter A. Ward4Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USAC5a is an inflammatory mediator generated by complement activation that positively regulates various arms of immune defense, including Toll-like receptor 4 (TLR4) signaling. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is activated by pathogen products and cellular/tissue damage products and is a major contributor of IL-1β. In this study, we investigate whether C5a modulates lipopolysaccharide- (LPS-) induced NLRP3 inflammasome activation in myeloid cells. Appearance of plasma IL-1β during endotoxemia was reduced in C5aR1-/- mice when compared to wild-type mice. In vitro, C5a significantly enhanced LPS-induced production of IL-1β in bone marrow Ly6C-high inflammatory monocytes, accompanied by augmented intracellular pro-IL-1β expression. This effect was abolished during p38 blockade by SB 203580 and in the absence of C5aR1. Conversely, C5a suppressed LPS-induced macrophage production of IL-1β, which was accompanied by attenuated levels of pro-IL-1β, NLRP3, and caspase-1 expression. C5a’s suppressive effects were negated during phosphoinositide 3-kinase (PI3K) inhibition by wortmannin but were largely preserved in the absence of C5aR1. Thus, C5a bidirectionally amplifies TLR4-mediated NLRP3 inflammasome activation in monocytes while suppressing this pathway in macrophages. However, as C5aR1 deficiency attenuates the IL-1β response to LPS challenge in vivo, our results suggest overall that C5a augments physiologic inflammasome responses.http://dx.doi.org/10.1155/2016/1340156 |
| spellingShingle | Mikel D. Haggadone Jamison J. Grailer Fatemeh Fattahi Firas S. Zetoune Peter A. Ward Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes Mediators of Inflammation |
| title | Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes |
| title_full | Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes |
| title_fullStr | Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes |
| title_full_unstemmed | Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes |
| title_short | Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes |
| title_sort | bidirectional crosstalk between c5a receptors and the nlrp3 inflammasome in macrophages and monocytes |
| url | http://dx.doi.org/10.1155/2016/1340156 |
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