Batf2/Irf1 Induces Inflammatory Responses in Classically Activated Macrophages, Lipopolysaccharides, and Mycobacterial Infection

Abstract

Basic leucine zipper transcription factor Batf2 is poorly described, whereas Batf and Batf3 have been shown to play essential roles in dendritic cell, T cell, and B cell development and regulation. Batf2 was drastically induced in IFN-γ–activated classical macrophages (M1) compared with unstimulated or IL-4–activated alternative macrophages (M2). Batf2 knockdown experiments from IFN-γ–activated macrophages and subsequent expression profiling demonstrated important roles for regulation of immune responses, inducing inflammatory and host-protective genes Tnf, Ccl5, and Nos2. Mycobacterium tuberculosis (Beijing strain HN878)–infected macrophages further induced Batf2 and augmented host-protective Batf2-dependent genes, particularly in M1, whose mechanism was suggested to be mediated through both TLR2 and TLR4 by LPS and heat-killed HN878 (HKTB) stimulation experiments. Irf1 binding motif was enriched in the promoters of Batf2-regulated genes. Coimmunoprecipitation study demonstrated Batf2 association with Irf1. Furthermore, Irf1 knockdown showed downregulation of IFN-γ– or LPS/HKTB-activated host-protective genes Tnf, Ccl5, Il12b, and Nos2. Conclusively, Batf2 is an activation marker gene for M1 involved in gene regulation of IFN-γ–activated classical macrophages, as well as LPS/HKTB-induced macrophage stimulation, possibly by Batf2/Irf1 gene induction. Taken together, these results underline the role of Batf2/Irf1 in inducing inflammatory responses in M. tuberculosis infection.

Petri Net computational modelling of Langerhans cell Interferon Regulatory Factor Network predicts their role in T cell activation

“…2b, all the conditions outlined have been met by the in silico model of the GRN. As reported by others, induction of Th1 responses required expression of either IRF1 alone or a combination of IRF8 and ETS transcriptional partners 26–28, 33 (Fig. 2a, Table S2), while expression of Th2/Th17 was critically dependent on simultaneous expression of IRF4:ETS 29–31 (Th2, Fig.…”

“…In essence, while the GRN architecture and main components are shared between different cell types, the spectrum of output genes regulated by the network varies with the specific cell type. This can be illustrated by the fact that although, for Th1-polarising dendritic cells, IRF1-controlled IL12p70 production appears established 26, 49 , we and others have demonstrated that IL12p70 is not produced by human LCs 2, 13, 50, 51 . This is despite the rapid up-regulation of IRF1 transcripts in LCs upon stimulation (Fig.…”

“…The approach allows the user to vary inputs, which then create a signal flow through the network based solely on the network connectivity, eliminating the necessity for multiple kinetic parameters at each step. The network model was first validated to recapitulate outcomes reported in the literature, including dendritic cells and macrophage subsets 26–35 . Subsequently they have been used to model experimental data derived from whole transcriptome analysis of human Langerhans cells.…”

An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets

“…It is therefore possible that IRF-1 contributes to type III IFN production in CVB3 infected islets via a positive feedback loop, and that the overall stronger type III IFN response in islets with the TC genotype is a result of a stronger positive feedback on type III IFN gene expression. The transcription factor BATF2 was recently shown to interact with IRF-1 and to positively influence the transcription of a subgroup of genes in IFNγ stimulated macrophages42. Our transcriptome analysis suggested that CVB3 infected islets with the TC genotype express more BATF2 mRNA than islets with the TT genotype (Fig.…”

Chronic Infection Depletes Hematopoietic Stem Cells through Stress-Induced Terminal Differentiation

“…Hematopoietic progenitors overexpressing Batf2 demonstrated a trend toward increased early myeloid differentiation 8 weeks after transplantation into lethally irradiated WT recipients (Figure 7C). Since Batf family members are known to act in cooperation with cofactors such as Irf1 (Roy et al, 2015), the observation that myeloid differentiation was even modestly increased without additional expression of cofactors was striking. In contrast to control cells overexpressing GFP alone, the overall engraftment of Batf2-overexpressing clones declined between 4 and 8 weeks post-transplant, showing that engraftment capacity is impaired (Figure 7D–E).…”