Cutting Edge: Synchronization of IRF1, JunB, and C/EBPβ Activities during TLR3–TLR7 Cross-Talk Orchestrates Timely Cytokine Synergy in the Proinflammatory Response

Abstract

Multiple pathogen-associated molecular pattern–induced TLR pathway cross-talk provokes proinflammatory cytokine synergy in macrophages, which is important for pathogen resistance and immune homeostasis. However, the detailed mechanisms are unclear. In this article, we demonstrate viral RNA analog–induced transcription synergy of Il6 and Il12b via IFN regulatory factor (IRF)1 (TLR3–TIR domain–containing adaptor inducing IFN-β [TRIF] responsive), C/EBPβ (TLR7-MyD88 responsive), and JunB (all responsive). Coactivation of the TLR3 and TLR7 pathways synchronizes the interaction of IRF1, JunB, and C/EBPβ with the Il6 and Il12b promoters, facilitating maximal gene expression. MyD88 pathway activation suppresses TRIF-induced IRF1 in a delayed manner, controlling the magnitude and timing of cytokine expression. Our findings provide novel mechanisms of cooperation of different TLR pathways to achieve optimal immune responses, with the potential for immunomodulatory strategies.

Genome-Wide Immune Modulation of TLR3-Mediated Inflammation in Intestinal Epithelial Cells Differs between Single and Multi-Strain Probiotic Combination

“…Increased TLR5 expression in TLR3-activated IEC is indicative of PRR cross-activation. The MYD88-TRIF adaptor cross-talk has been shown to synergize the immune response in the presence of TLR3 and TLR4 or TLR9 ligands and can act as a secondary signal to help the host evaluate an appropriate response to an immune challenge [36,37]. In contrast to Lh-R0052, Lh-R0052-SLP co-challenge increased the expression of the inflammasome component NLRC4 (NLR family, CARD domain containing 4), demonstrating purified components from a probiotic strain can differ in their mechanism of action from whole bacteria.…”

Innate immune memory and homeostasis may be conferred through crosstalk between the TLR3 and TLR7 pathways

“…We revealed the dual opposing roles of the JAK-STAT pathway: STAT1 induces the expression of genes encoding inflammatory cytokines through transcription factors such as IRF1 (28), whereas it also inhibits cytokine production through its target, the anti-inflammatory cytokine IL-10. The overall extent of cytokine production depended on the subtle, time-dependent coordination of IRF1 and IL-10.…”

“…Synergistic cytokine production induced by the collaboration of multiple TLRs plays an important role in mounting effective immune responses and pathogen clearance. Conversely, overreactive immune responses due to TLR crosstalk (13, 28), if unchecked, would also harm the host, causing chronic or acute inflammation. For example, increased amounts of IL-6, IL-12p40, and IL-12p19 are observed in the serum of systemic lupus erythematosus patients, as well as in mouse models (53, 54), and such autoimmune disorders are closely related to TLR3-and TLR7-mediated responses.…”

Innate Control of Adaptive Immunity: Beyond the Three-Signal Paradigm

“…TLR3 and TLR4 synergize with TLR7, TLR8 and TLR9 to enhance the production of IL-12 and IL-23, and Th1 driving capacity of DCs(49). Cooperation between PRRs has been shown to result in unique transcriptional changes, which control the quality, quantity and kinetics of chemokine and cytokine production(50). One very well-known example of such PRRs synergy is inflammasome activation by virulent pathogens.…”