Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-loaded macrophages in the arterial wall. Intimal macrophages internalize modified lipoproteins such as oxidized LDL (oxLDL) through scavenger receptors, leading to storage of excess cholesteryl esters in lipid bodies and a "foam cell" phenotype. In addition, stimulation of macrophage Toll-like receptors (TLRs) has been shown to promote lipid body proliferation. We investigated the possibility that there are transcriptional regulators that are common to both pathways for stimulating foam cell formation (modified lipoproteins and TLR stimulation), and identified the transcription factor ATF3 as a candidate regulator.
ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol-induced lipid body formation.
Sex, Specimen part
View SamplesThe innate immune system is a two-edged sword; it is absolutely required for host defense against infection, but if left uncontrolled can trigger a plethora of inflammatory diseases. Here we used systems biology approaches to predict and validate a gene regulatory network involving a dynamic interplay between the transcription factors NF-B, C/EBP, and ATF3 that controls inflammatory responses. We mathematically modeled transcriptional regulation of Il6 and Cebpd genes and experimentally validated the prediction that the combination of an initiator (NF-B), an amplifier (C/EBP) and an attenuator (ATF3) forms a regulatory circuit that discriminates between transient and persistent Toll-like receptor 4-induced signals. Our results suggest a mechanism that enables the innate immune system to detect the duration of infection and to respond appropriately.
Function of C/EBPdelta in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals.
Sex, Specimen part
View SamplesMicroarray experiments were performed using FAC-sorted young photoreceptors to analyze their transcriptome in comparison to remaining retinal cells at same developmental stage and retinal progenitors.
Increased integration of transplanted CD73-positive photoreceptor precursors into adult mouse retina.
Specimen part
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