Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, 10021, USA.
Department of Biology, Chungbuk National University, Cheongju, 28644, Republic of Korea.
Nat Commun. 2019 Jul 25;10(1):3320. doi: 10.1038/s41467-019-11147-3.
Activation of macrophage proinflammatory and antimicrobial phenotypes is regulated by IFN-γ and LPS via synergistic induction of canonical, inflammatory NF-κB target genes. However, whether IFN-γ negatively regulates components of the LPS response, and how this may affect macrophage activation, is still unclear. Here we use combined transcriptomic and epigenomic approaches to find that IFN-γ selectively abrogates LPS-induced feedback and alters macrophage metabolic pathways by suppressing TLR4-mediated gene activation. In contrast to superinduction of inflammatory genes via enhancers that bind IRF1 and STAT1, IFN-γ represses target enhancers that bind STAT3. TLR4-activated but IFN-γ-suppressed enhancers comprise two subsets discernable by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin. Our findings thus show that IFN-γ suppresses feedback inhibitory and metabolic components of TLR responses to enhance macrophage activation; they also provide insights for IFN-γ-mediated selective inhibition of TLR4-induced transcription. Such inhibition can contribute to severe and sustained inflammatory responses.
巨噬细胞促炎和抗菌表型的激活受 IFN-γ 和 LPS 调控，通过协同诱导经典炎症 NF-κB 靶基因。然而，IFN-γ 是否负调控 LPS 反应的成分，以及这如何影响巨噬细胞的激活，仍不清楚。在这里，我们使用组合转录组学和表观基因组学方法发现，IFN-γ 通过抑制 TLR4 介导的基因激活，选择性地消除 LPS 诱导的反馈并改变巨噬细胞代谢途径。与通过结合 IRF1 和 STAT1 的增强子对炎症基因的超诱导相反，IFN-γ 抑制结合 STAT3 的靶增强子。TLR4 激活但 IFN-γ 抑制的增强子由两个亚组组成，可通过组蛋白乙酰化的差异调节和 STAT3、CDK8 和共蛋白的募集来区分。因此，我们的发现表明，IFN-γ 抑制 TLR 反应的反馈抑制和代谢成分，以增强巨噬细胞的激活；它们还为 IFN-γ 介导的 TLR4 诱导转录的选择性抑制提供了见解。这种抑制可能导致严重和持续的炎症反应。
