Activating transcription factor 3 modulates the macrophage immune response toMycobacterium tuberculosisinfection via reciprocal regulation of inflammatory genes and lipid body formation

Abstract

Infection of macrophages by Mycobacterium tuberculosis elicits an immune response that clears the bacterium. However, the bacterium is able to subvert the innate immune response. Differential expression of transcription factors (TFs) is central to the dynamic balance of this interaction. Among other functions, TFs regulate the production of antibacterial agents such as nitric oxide, pro-inflammatory cytokines and neutral lipids which are stored in lipid bodies (LBs) and favour bacterial survival. Here, we demonstrate that the TF activating transcription factor 3 (ATF3) is upregulated early during infection of macrophages or mice. Depletion of ATF3 enhances mycobacterial survival in macrophages suggesting its host-protective role. ATF3 interacts with chromatin remodelling protein brahma-related gene 1 and both associate with the promoters of interleukin-12p40, interleukin-6 and nitric oxide synthase 2, to activate expression of these genes. Strikingly, ATF3 downregulates LB formation by associating at the promoters of positive regulators of LB formation such as cholesterol 25 hydroxylase and the microRNA-33 locus. ATF3 represses the association of the activating mark, acetyl histone H4 lysine 8 at the promoter of cholesterol 25 hydroxylase. Our study suggests opposing roles of ATF3 in regulation of distinct sets of macrophage genes during infection, converging on a host-protective immune response.

Meta-Analysis of Peripheral Blood Transcriptome Datasets Reveals a Biomarker Panel for Tuberculosis in Patients Infected With HIV

“…Moreover, in the mouse model, ATF3 was expressed in macrophages infected with Mycobacterium tuberculosis (Seimon et al, 2010). ATF3 regulates the immune response of macrophages to Mycobacterium tuberculosis infection through the formation of inflammatory genes and liposomes (Kumar et al, 2020). The combination of these four genes identified in our meta-analysis study predicted TB with a higher AUC in patients with HIV, and therefore form a valuable biomarker panel.…”

Blood transcriptomics identifies immune signatures indicative of infectious complications in childhood cancer patients with febrile neutropenia

“…4 We identified almost 500 genes that were differentially expressed and distinguished infectious causes of FN from unexplained fever. Amongst the top differentially expressed genes was ATF3 (activating transcription factor 3), a transcription factor that modulates immune response by negatively regulating inflammatory genes, calcium signalling and lysosome formation [12][13][14] and was shown to provide protection against bacterial infections. 15 Genes involved in phagocytosis and lysosome/vesicle formation are key pathways involved in early innate responses to infection and were also differentially regulated between infectious and non-infectious causes of FN in our study.…”

Extracellular HMGB1 as Inflammatory Mediator in the Progression of Mycoplasma Gallisepticum Infection

“…TLR2/TLR4 participate in a variety of immune regulation as typical HMGB1 receptors [ 56 ]. The immune system eliminates pathogens by secreting massive amounts of cytokines [ 57 ]. However, secretory HMGB1 exerts excessive activation of immune cells, induces overexpression of pro-inflammatory cytokines, and triggers immune disorders [ 58 ].…”