| First Author | Rhoads JP | Year | 2017 |
| Journal | J Immunol | Volume | 198 |
| Issue | 5 | Pages | 2105-2114 |
| PubMed ID | 28130494 | Mgi Jnum | J:247745 |
| Mgi Id | MGI:5926089 | Doi | 10.4049/jimmunol.1601563 |
| Citation | Rhoads JP, et al. (2017) Oxidized Low-Density Lipoprotein Immune Complex Priming of the Nlrp3 Inflammasome Involves TLR and FcgammaR Cooperation and Is Dependent on CARD9. J Immunol 198(5):2105-2114 |
| abstractText | Oxidized low-density lipoprotein (oxLDL) is known to activate inflammatory responses in a variety of cells, especially macrophages and dendritic cells. Interestingly, much of the oxLDL in circulation is complexed to Abs, and these resulting immune complexes (ICs) are a prominent feature of chronic inflammatory disease, such as atherosclerosis, type-2 diabetes, systemic lupus erythematosus, and rheumatoid arthritis. Levels of oxLDL ICs often correlate with disease severity, and studies demonstrated that oxLDL ICs elicit potent inflammatory responses in macrophages. In this article, we show that bone marrow-derived dendritic cells (BMDCs) incubated with oxLDL ICs for 24 h secrete significantly more IL-1beta compared with BMDCs treated with free oxLDL, whereas there was no difference in levels of TNF-alpha or IL-6. Treatment of BMDCs with oxLDL ICs increased expression of inflammasome-related genes Il1a, Il1b, and Nlrp3, and pretreatment with a caspase 1 inhibitor decreased IL-1beta secretion in response to oxLDL ICs. This inflammasome priming was due to oxLDL IC signaling via multiple receptors, because inhibition of CD36, TLR4, and FcgammaR significantly decreased IL-1beta secretion in response to oxLDL ICs. Signaling through these receptors converged on the adaptor protein CARD9, a component of the CARD9-Bcl10-MALT1 signalosome complex involved in NF-kappaB translocation. Finally, oxLDL IC-mediated IL-1beta production resulted in increased Th17 polarization and cytokine secretion. Collectively, these data demonstrate that oxLDL ICs induce inflammasome activation through a separate and more robust mechanism than oxLDL alone and that these ICs may be immunomodulatory in chronic disease and not just biomarkers of severity. |
