Research progress on the effect of traditional Chinese medicine on the activation of PRRs-mediated NF-κB signaling pathway to inhibit influenza pneumonia

Abstract

Influenza pneumonia has challenged public health and social development. One of the hallmarks of severe influenza pneumonia is overproduction of pro-inflammatory cytokines and chemokines, which result from the continuous activation of intracellular signaling pathways, such as the NF-κB pathway, mediated by the interplay between viruses and host pattern recognition receptors (PRRs). It has been reported that traditional Chinese medicines (TCMs) can not only inhibit viral replication and inflammatory responses but also affect the expression of key components of PRRs and NF-κB signaling pathways. However, whether the antiviral and anti-inflammatory roles of TCM are related with its effects on NF-κB signaling pathway activated by PRRs remains unclear. Here, we reviewed the mechanism of PRRs-mediated activation of NF-κB signaling pathway following influenza virus infection and summarized the influence of anti-influenza TCMs on inflammatory responses and the PRRs/NF-κB signaling pathway, so as to provide better understanding of the mode of action of TCMs in the treatment of influenza pneumonia.

Keywords: NF-κB signaling pathway; TCM; influenza viruses; pattern recognition receptor; viral pneumonia.

FIGURE 1

Potential mechanisms of anti-influenza TCMs in treatment of influenza pneumonia via TLRs/RIG-I signaling pathway. Influenza virus infection is detected by multiple PRRs such as TLRs and RIG-I. TLR3 recruits TIR-domain-containing adapter-inducing interferon-β (TRIF) and the endocytosed TLR4 recruits TRIF and TRIF-related adaptor molecule (TRAM), which activates TRIF-dependent pathway. The interaction between TRIF and TNF receptor-associated factor 6 (TRAF6) recruits the receptor-interacting protein 1 (RIP1) and activates the transforming growth factor β-activated kinase 1 (TAK1)/TAK1-binding protein (TAB) complex that leads to activation of NF-κB and downstream transcription of pro-inflammatory genes. Alternatively, TRIF interacts with TRAF3 and recruits TANK (TRAF family member associated NF-κB activator)-binding kinase 1 (TBK1) and the inhibitor of NF-κB (IκB) kinase ε (IKKε), which drives the phosphorylation of the interferon regulatory factor 3 (IRF3) or IRF7 and downstream production of type I interferons (IFNs). TLR3 recognizes dsRNA in endosomes, but it recognizes currently unknown RNA structures presenting in influenza virus-infected cells (presented in dotted line). TLR4, TLR7, and TLR8 initiate downstream signaling through the adapter protein myeloid differentiation primary response differentiation gene 88 (MyD88)-dependent pathway. For TLR4, it uses TIR domain containing adaptor protein (TIRAP) as additional adapter in this pathway. TLR7 recognizes the ssRNA genomes of influenza virus taken up into the endosome. The activation of MyD88 leads to the phosphorylation of IL-1R-associated kinases 1 and 4 (IRAK1/4) which binds with TRAF6 to mediate the activation of TAK1/TAB complex, and then induces the translocation of NF-κB to regulate the expression of cytokines and chemokines. RIG-I mainly recognizes viral nucleocapsids and viral genomic RNA bearing 5′-ppp. It connects to MAVS which then assembles with TRAF2/3/6, TBK1, and IKK complex to function as a signaling hub that drives the activation of IRF3, IRF7, and NF-κB and downstream production of IFNs and proinflammatory cytokines and chemokines. A variety of TCMs could regulate the expression of key components in TLRs/RIG-I signaling pathways so as to inhibit viral replication and virus-induced pro-inflammatory response.