OxLDL inhibits LPS-induced IFNβ expression by Pellino3- and IRAK1/4-dependent modification of TANK

Abstract

In atherosclerosis macrophages contribute to disease progression. After infiltrating atherosclerotic lesions they accumulate oxLDL (oxidized low density lipoproteins) and differentiate into foam cells. During this process inhibition of TLR4 (Toll-like receptor 4)-dependent IFNβ expression occurs. To understand molecular mechanisms how oxLDL inhibits LPS-induced IFNβ expression in macrophage-derived foam cells, we analyzed the impact of oxLDL on signaling pathways upstream of IFNβ expression. We identified mono-ubiquitination of TANK (TRAF family member-associated NFκB activator), a scaffold protein of the TRIF (TIR-domain-containing adapter-inducing IFNβ)-dependent TLR4-signaling cascade. Modified TANK inhibits recruitment of TBK1 (TANK-binding kinase 1) to TRAF3 (TNF receptor associated factor 3) and the subsequent activation of the transcription factor IRF3 (interferon regulatory factor 3). OxLDL stimulates TANK mono-ubiquitination by subsequent activation of IRAK1/4 (interleukin-1 receptor-associated kinases 1 and 4) and Pellino3 downstream of SR-A1 (scavenger receptor-A1). Our observations highlight the regulatory impact of IRAK1/4 and Pellino3 on the TRIF-dependent TLR4-signaling cascade, which might be of general importance for disease conditions associated with macrophage pathologies such as atherosclerosis.