| First Author | Niemi K | Year | 2011 |
| Journal | J Immunol | Volume | 186 |
| Issue | 11 | Pages | 6119-28 |
| PubMed ID | 21508263 | Mgi Jnum | J:173210 |
| Mgi Id | MGI:5013542 | Doi | 10.4049/jimmunol.1002843 |
| Citation | Niemi K, et al. (2011) Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway. J Immunol 186(11):6119-28 |
| abstractText | Serum amyloid A (SAA) is an acute-phase protein, the serum levels of which can increase up to 1000-fold during inflammation. SAA has a pathogenic role in amyloid A-type amyloidosis, and increased serum levels of SAA correlate with the risk for cardiovascular diseases. IL-1beta is a key proinflammatory cytokine, and its secretion is strictly controlled by the inflammasomes. We studied the role of SAA in the regulation of IL-1beta production and activation of the inflammasome cascade in human and mouse macrophages, as well as in THP-1 cells. SAA could provide a signal for the induction of pro-IL-1beta expression and for inflammasome activation, resulting in secretion of mature IL-1beta. Blocking TLR2 and TLR4 attenuated SAA-induced expression of IL1B, whereas inhibition of caspase-1 and the ATP receptor P2X(7) abrogated the release of mature IL-1beta. NLRP3 inflammasome consists of the NLRP3 receptor and the adaptor protein apoptosis-associated speck-like protein containing CARD (a caspase-recruitment domain) (ASC). SAA-mediated IL-1beta secretion was markedly reduced in ASC(-/-) macrophages, and silencing NLRP3 decreased IL-1beta secretion, confirming NLRP3 as the SAA-responsive inflammasome. Inflammasome activation was dependent on cathepsin B activity, but it was not associated with lysosomal destabilization. SAA also induced secretion of cathepsin B and ASC. In conclusion, SAA can induce the expression of pro-IL-1beta and activation of the NLRP3 inflammasome via P2X(7) receptor and a cathepsin B-sensitive pathway. Thus, during systemic inflammation, SAA may promote the production of IL-1beta in tissues. Furthermore, the SAA-induced secretion of active cathepsin B may lead to extracellular processing of SAA and, thus, potentially to the development of amyloid A amyloidosis. |
