Roles of Toll-Like Receptors in Nitroxidative Stress in Mammals

Abstract

Free radicals are important antimicrobial effectors that cause damage to DNA, membrane lipids, and proteins. Professional phagocytes produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) that contribute towards the destruction of pathogens. Toll-like receptors (TLRs) play a fundamental role in the innate immune response and respond to conserved microbial products and endogenous molecules resulting from cellular damage to elicit an effective defense against invading pathogens, tissue injury, or cancer. In recent years, several studies have focused on how the TLR-mediated activation of innate immune cells leads to the production of pro-inflammatory factors upon pathogen invasion. Here, we review recent findings that indicate that TLRs trigger a signaling cascade that induces the production of reactive oxygen and nitrogen species.

Keywords: antimicrobial; free radicals; toll-like receptors.

Figure 1

MYD88-dependent pathway (left). MYD88-independent pathways (right) [52].

Figure 2

The TLR2 signal pathway involved in oxidative stress [48,55]. The TLR2 signaling pathway activates the MYD88 pathway to activate the NF-κB and MAPK pathways under the action of the ligand Pam3CSK4. Phosphorylation of MAPK then activates transcription factor activator protein-1 (AP-1) and PI3K/protein kinase signaling pathways to induce an immune response. AP-1 is a transcription factor that mediates pro-inflammatory factors, and NO^● levels are regulated by iNOS. Nrf2 can induce the expression of pro-inflammatory factors by inhibiting the expression of pro-inflammatory NF-κB, which is a rate-limiting enzyme involved in the anti-inflammatory reaction and can induce oxidative stress. GSH, SOD, and CAT are all in a key antioxidant in the host organism. Activated NF-κB reduces cellular SOD activity.

Figure 3

TLR4 signal pathway in oxidative stress [73,75]. TLR4 interacts with myeloid differentiation factor 2 (MD2), CD14, and specific ligand LPS receptors, then recruits downstream adaptors to activate MyD88− and TRIF-dependent pathway-mediated IRAK4-dependent NF-κB, which can trigger the transcription-promoting NO^●. The GCHI-iNOS gene shows a significant increase in the expression of iNOS and NO, which accelerates the inflammatory response by reducing SOD activity and increasing MDA production. GSH eliminates free radicals and prevents oxidative damage.