Natural Products with Toll-Like Receptor 4 Antagonist Activity

Abstract

Toll-Like Receptors (TLRs) are the innate immunity receptors that play an activating role when interacting with molecules released by bacteria and viruses (PAMPs, pathogen-associated molecular patterns) or with molecules released by injured cells and tissues (DAMPs, danger-associated molecular patterns). TLR triggering leads to the induction of proinflammatory cytokines and chemokines, driving the activation of both innate and adaptive immunity. In particular, Toll-Like Receptor 4 (TLR4) has been described to be involved in the inflammatory processes observed in several pathologies (such as ischemia/reperfusion injury, neuropathic pain, neurodegenerative diseases, and cancer). Molecules obtained by natural sources have been discovered to exert an anti-inflammatory action by targeting TLR4 activation pathways. This review focuses on TLR4 antagonists obtained from bacteria, cyanobacteria, and plants.

Figure 1

TLR4 intracellular signaling pathways. TLR4 signaling is induced by interaction with the specific ligand (e.g., LPS). In detail, LPS binding to MD-2 promotes dimerization of TLR4/MD-2 with the recruitment of intracellular adaptor proteins, MyD88 and TIRAP (MyD88-dependent pathway) or TRIF and TRAM (MyD88-independent pathway). In MyD88-dependent pathway, there is the recruitment and activation of IRAKs and TRAF6, inducing TAK1 activation. TAK1 coupling to the IKK complex and NEMO leads to IkB phosphorylation and nuclear translocation of NF-κB. TAK1-dependent activation of MKKs promotes AP-1 transcription factor induction. In MyD88-independent pathway TRIF and TRAM adaptor proteins are involved in the activation of TRAF3 and, downstream, in the induction of TBK1 and IKKε, needed for the activation of the transcription factor IRF3.

Figure 2

Structure of lipid A from Rhodobacter sphaeroides. Source: [22], under Creative Commons Attribution 4.0 International License.

Figure 3

Proposed structure of LOS from Bartonella quintana. Source: [23], under Creative Common Attribution 4.0 International License.

Figure 4

Proposed structure of lipid A from Oscillatoria Planktothrix FP1.

Figure 5

Structure of curcumin (a) and sulforaphane (b), xanthohumol (c), and celastrol (d). Sources: curcumin structure: [24], under Creative Commons Noncommercial No Derivative Works (CC-BY-NC-ND) Attribution License. Sulforaphane structure: [25], under Creative Commons Attribution 4.0 International License. Xanthohumol structure: [26], under Creative Commons Attribution License (CC-BY). Celastrol structure: [27], under Creative Commons License (CC-BY).