TRIF Regulates BIC/miR-155 via the ERK Signaling Pathway to Control the ox-LDL-Induced Macrophage Inflammatory Response

Abstract

Toll/IL-1R-domain-containing adaptor-inducing IFN-β (TRIF) is an important adaptor for TLR3- and TLR4-mediated inflammatory signaling pathways. Recent studies have shown that TRIF plays a key role in vessel inflammation and atherosclerosis; however, the precise mechanisms are unclear. We investigated the mechanisms of the TRIF-regulated inflammatory response in RAW264.7 macrophages under oxidized low-density lipoprotein (ox-LDL) stimulation. Our data show that ox-LDL induces TRIF, miR-155, and BIC expression, activates the ERK1/2 and SOCS1-STAT3-NF-κB signaling pathways, and elevates the levels of IL-6 and TNF-α in RAW264.7 cells. Knockdown of TRIF using TRIF siRNA suppressed BIC, miR-155, IL-6, and TNF-α expression and inhibited the ERK1/2 and SOCS1-STAT3-NF-κB signaling pathways. Inhibition of ERK1/2 signaling also suppressed BIC and miR-155 expression. These findings suggest that TRIF plays an important role in regulating the ox-LDL-induced macrophage inflammatory response and that TRIF modulates the expression of BIC/miR-155 and the downstream SOCS1-STAT3-NF-κB signaling pathway via ERK1/2. Therefore, TRIF might be a novel therapeutic target for atherosclerosis.

Monocytes reprogrammed by 4-PBA potently contribute to the resolution of inflammation and atherosclerosis

“…Our functional data further validated that TRAM may serve as a general membrane stress sensor for monocyte activation given that the induction of ICAM-1 and CCL5 by oxLDL is ablated in TRAM-deficient monocytes. Our data can also reconciles previous independent findings that implicate TRAM as a key signaling adaptor for oxidized phospholipid-induced monocyte activation 63,64 . Our data demonstrating the role of 4-PBA in alleviating TRAM clustering and reducing monocyte inflammatory polarization suggest that additional compounds that relieve membrane stress may be similarly effective in dampening monocyte low-grade inflammatory memory.…”

MicroRNA‐155 inhibits dengue virus replication by inducing heme oxygenase‐1‐mediated antiviral interferon responses

“…17 Over time, the effects of host miRNAs on the life cycle of the virus have gradually been elucidated. [18][19][20] Recently, miR-155 has received significant attention because it is abundantly expressed in activated lymphocytes 21 and macrophages 22 and has been characterized as an important factor regulating T helper cell differentiation, 23 the macrophage response, 24 and pro-inflammatory transcription programs, and modulating microglia-mediated innate immune responses. 25,26 In addition, miR-155 is a TNFα-inducible microRNA predicted to bind to BACH1 mRNA, which mediates the effect of TNFα on endothelial HO-1 expression.…”

Golgi apparatus fragmentation participates in oxidized low‐density lipoprotein‐induced endothelial cell injury

“…30,31 Moreover, ox-LDL has been confirmed to induce macrophage inflammatory response via activating ERK pathway. 32 Takemura et al 33 also suggested that ox-LDL exposure led to ERK1/2 activation in cultured human endothelial cells. Based on these previous findings, we speculate that the ERK pathway might be involved in ox-LDL-induced GA fragmentation.…”

“…Cdk1/cyclinB1 during mitosis causes the activation of ERK and subsequent phosphorylation of GRASP65 at Ser277 . Moreover, ox‐LDL has been confirmed to induce macrophage inflammatory response via activating ERK pathway . Takemura et al also suggested that ox‐LDL exposure led to ERK1/2 activation in cultured human endothelial cells.…”