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The Toll like receptors (TLRs) and the type I interferons have critical roles to play in innate immunity. In this review we will discuss new developments relating to the important area of TLR/IFN cross regulation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

IL-33, a member of the IL-1 family of cytokines, is produced by many cell types, including macrophages, yet its regulation is largely unknown. Treatment of primary murine macrophages with a panel of TLR (e.g., TLR2, TLR3, TLR4, and TLR9) agonists and non-TLR (e.g., MDA5, RIG-I) agonists revealed a pattern of gene and protein expression consistent with a role for IFN regulatory factor-3 (IRF-3) in the expression of IL-33. Accordingly, induction of IL-33 mRNA was attenuated in IRF-3(-/-) macrophages and TBK-1(-/-) mouse embryonic fibroblasts. Despite the fact that all IL-33 agonists were IRF-3 dependent, LPS-induced IL-33 mRNA was fully inducible in IFN-β(-/-) macrophages, indicating that IL-33 is not dependent on IFN-β as an intermediate. Epinephrine and Bordetella pertussis adenylate cyclase toxin (ACT), cAMP-activating agents, activate CREB and greatly synergize with LPS to induce IL-33 mRNA in macrophages. Both LPS-induced and ACT/LPS-enhanced expression of IL-33 mRNA was partially, but significantly, inhibited by the protein kinase A inhibitor H-89 but not by tyrosine kinase or protein kinase C inhibitors. Two IL-33 mRNA species derived from two alternative promoters encode full-length IL-33; however, the shorter "A" species is preferentially induced by all IL-33-inducing agonists except Newcastle disease virus, a RIG-I agonist that induced expression of both "A" and "B" transcripts. Together, these studies greatly extend what is currently known about the regulation of IL-33 induction in macrophages stimulated by bacterial and viral agonists that engage distinct innate immune signaling pathways.

Toll-like receptors (TLRs) are major receptors of the host innate immune system that recognize conserved pathogen-associated molecular patterns (PAMPs) of invading microbes. Activation of TLR signaling culminates in the expression of multiple genes in a coordinate and kinetically defined manner. In this review, we summarize the current studies describing the chromatin landscape of TLR-responsive inflammatory genes and how changes to this chromatin landscape govern cell type-specific and temporal gene expression. We further elaborate classical endotoxin tolerance and epigenetic mechanisms controlling tolerance and interferon priming effects on inflammatory promoters. [ABSTRACT FROM AUTHOR]

The innate inflammatory response to Francisella tularensis (Ft) in macrophages is significantly governed by the expression of type I interferon (IFN). Previously, the proteolytic processing and maturation of pro-IL-1β protein was shown to depend upon type I IFN expression. We show in this report that paracrine type I IFN can profoundly enhance innate recognition and TLR-dependent transcriptional responses to Ft infection upstream of its role in inflammasome regulation in both primary human monocyte-derived macrophages and primary murine peritoneal macrophages but not murine bone marrow-derived macrophages. This type I IFN-enhanced response is synergistic with TLR2 transcriptional responses, partially TLR2-independent, but strictly MyD88-dependent. [ABSTRACT FROM AUTHOR]

The cell surface/endosomal Toll-like Receptors (TLRs) are instrumental in initiating immune responses to both bacteria and viruses. With the exception of TLR2, all TLRs and cytosolic RIG-I-like receptors (RLRs) with known virus-derived ligands induce type I interferons (IFNs) in macrophages or dendritic cells. Herein, we report that prior ligation of TLR2, an event previously shown to induce “homo” or “hetero” tolerance, strongly “primes” macrophages for increased Type I IFN production in response to subsequent TLR/RLR signaling. This occurs by increasing activation of the transcription factor, IFN Regulatory Factor-3 (IRF-3) that, in turn, leads to enhanced induction of IFN-β, while expression of other pro-inflammatory genes are suppressed (tolerized). In vitro or in vivo “priming” of murine macrophages with TLR2 ligands increase virus-mediated IFN induction and resistance to infection. This priming effect of TLR2 is mediated by the selective upregulation of the K63 ubiquitin ligase, TRAF3. Thus, we provide a mechanistic explanation for the observed antiviral actions of MyD88-dependent TLR2 and further define the role of TRAF3 in viral innate immunity. [ABSTRACT FROM AUTHOR]

The selective utilization of IRAK kinases, which are thought to be recruited to MyD88 to form the ‘Myddosome’, has been shown to differ substantially in mouse and human cells. This finding has important implications for the development of therapeutics for inflammatory and autoimmune disorders associated with Toll-like receptors. [ABSTRACT FROM AUTHOR]