941.full.pdf (2.26 MB)
TPL-2 inhibits IFN-β expression via an ERK1/2-TCF-FOS axis in TLR4-stimulated macrophages.
journal contributionposted on 2022-02-08, 14:19 authored by Louise Blair, Michael J Pattison, Probir Chakravarty, Stamatia Papoutsopoulou, Latifa Bakiri, Erwin F Wagner, Stephen Smale, Steven C Ley
TPL-2 kinase plays an important role in innate immunity, activating ERK1/2 MAPKs in myeloid cells following TLR stimulation. We investigated how TPL-2 controls transcription in TLR4-stimulated mouse macrophages. TPL-2 activation of ERK1/2 regulated expression of genes encoding transcription factors, cytokines, chemokines, and signaling regulators. Bioinformatics analysis of gene clusters most rapidly induced by TPL-2 suggested that their transcription was mediated by the ternary complex factor (TCF) and FOS transcription factor families. Consistently, TPL-2 induced ERK1/2 phosphorylation of the ELK1 TCF and the expression of TCF target genes. Furthermore, transcriptomic analysis of TCF-deficient macrophages demonstrated that TCFs mediate approximately half of the transcriptional output of TPL-2 signaling, partially via induced expression of secondary transcription factors. TPL-2 signaling and TCFs were required for maximal TLR4-induced FOS expression. Comparative analysis of the transcriptome of TLR4-stimulated Fos -/- macrophages indicated that TPL-2 regulated a significant fraction of genes by controlling FOS expression levels. A key function of this ERK1/2-TCF-FOS pathway was to mediate TPL-2 suppression of type I IFN signaling, which is essential for host resistance against intracellular bacterial infection.
Crick (Grant ID: 10103, Grant title: Ley FC001103) Crick (Grant ID: 10002, Grant title: STP Bioinformatics & Biostatistics) Medical Research Council (Grant ID: MR/M016358/1, Grant title: MRC MR/M016358/1)