| First Author | Haggadone MD | Year | 2016 |
| Journal | Mediators Inflamm | Volume | 2016 |
| Pages | 1340156 | PubMed ID | 27382187 |
| Mgi Jnum | J:319197 | Mgi Id | MGI:6863122 |
| Doi | 10.1155/2016/1340156 | Citation | Haggadone MD, et al. (2016) Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes. Mediators Inflamm 2016:1340156 |
| abstractText | 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-1beta. In this study, we investigate whether C5a modulates lipopolysaccharide- (LPS-) induced NLRP3 inflammasome activation in myeloid cells. Appearance of plasma IL-1beta during endotoxemia was reduced in C5aR1(-/-) mice when compared to wild-type mice. In vitro, C5a significantly enhanced LPS-induced production of IL-1beta in bone marrow Ly6C-high inflammatory monocytes, accompanied by augmented intracellular pro-IL-1beta 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-1beta, which was accompanied by attenuated levels of pro-IL-1beta, 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-1beta response to LPS challenge in vivo, our results suggest overall that C5a augments physiologic inflammasome responses. |
