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

Abstract

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and stimulate the innate immune response through the production of cytokines. The innate immune response depends on the timing of encountering PAMPs, suggesting a short-term “memory.” In particular, activation of TLR3 appears to prime macrophages for the subsequent activation of TLR7, which leads to synergistically increased production of cytokines. By developing a calibrated mathematical model for the kinetics of TLR3 and TLR7 pathway crosstalk and providing experimental validation, we demonstrated the involvement of the Janus-activated kinase (JAK)–signal transducer and activator of transcription (STAT) pathway in controlling the synergistic production of cytokines. Signaling through this pathway played a dual role: It mediated the synergistic production of cytokines, thus boosting the immune response, and it also maintained homeostasis to avoid an excessive inflammatory response. Thus, we propose that the JAK-STAT pathway provides a cytokine rheostat mechanism, which enables macrophages to fine-tune their responses to multiple, temporally separated infection events involving the TLR3 and TLR7 pathways.

Molecular Mechanisms That Underlie the Dynamic Adaptation of Innate Monocyte Memory to Varying Stimulant Strength of TLR Ligands

“…This is in consistent with some previous reports that demonstrated the lack of tolerance in monocytes/macrophages treated with TLR3 agonist. For example, a previous study with RAW264.7 cells revealed that the pretreatment with Poly I:C led to increased IL-12 production following a subsequent LPS stimulation (43, 44). At the translational level, low-grade inflammatory monocyte adaptation by TLR3 agonist may serve as a potential strategy to boost immune surveillance of tumor.…”

“…Cells were washed with cold PBS after specified treatments and harvested in SDS lysis buffer containing protease and phosphatase inhibitors as previously described (21, 44). Protein concentration was assessed by Bradford assay.…”

The molecular mechanisms of TLR‐signaling cooperation in cytokine regulation

“…Knowledge on the networking principles of PRRs, and the predicted and testable pathways could help us understand the sentinels of frontline immune defense and pathogenesis, and provide us with clues to control infection‐inflammation‐mediated diseases. Such an effort is ongoing collaboratively among empirical and computational experts 43 …”

Epigenetic Treatment of Persistent Viral Infections

“…For example, the mitochondrial antiviral signaling protein (MAVS) [Cao et al, 2016;Sun et al, 2016], which acts as a common adaptor molecule for RIG-I-like receptors that include melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 proteins (LGP2; Figure 2), is also known as adaptor protein interferon-b (IFNb) promoter stimulator 1 [Onomoto et al, 2014], virusinduced signaling adaptor protein (VISA) [Xu et al, 2005], and CARD adaptor inducing IFN-b (Cardif) [Meylan et al, 2005;Cao et al, 2016;Liu et al, 2016a;Xing et al, 2016]. Nonetheless, in addition to MAVS, several studies have implicated signaling pathways involving cellular nuclear factor kappaB (NF-jB) [Cao et al, 2016;Jha et al, 2016;Liu et al, 2016a] and the stimulator of IFN genes (STING, also known as MITA/ ERIS/MPYS [Onomoto et al, 2014;Liu et al, 2016c]) [Paludan et al, 2011;White et al, 2014;Weinberg et al, 2015;Barrat et al, 2016;Cherry et al, 2016], as well as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) [Gjyshi et al, 2015;Morris et al, 2016]. Proapoptotic proteins, including B-cell lymphoma-associated protein 2 (BCL2)-associated X protein (BAX) [Ohta and Nishiyama, 2011;Weinberg et al, 2015;Gross, 2016;Sun et al, 2016;Thomas and Gale, 2016], are also essential players in mounting a defense.…”

“…Retinoic acid inducible gene‐I (RIG‐I) is a caspase recruitment domain (CARD) containing protein that acts as an intracellular RNA receptor. When it detects the presence of cytoplasmic viral nucleic acids and other pathogens, it triggers innate immunity and signals the initiation of the immune response against RNA virus infection [Barrat et al, ; Liu et al, ]. The means by which mitochondria take charge of antiviral innate immune responses have not been fully characterized, and the multiple names given to some genes and their protein products involved in the signaling pathways can be confusing.…”