Herbs And Phytochemicals: Corilagin From Hypophyllum Eliminates Macrophages Inflammation In Atherosclerosis Through TLR4-NFκB/MAPK Pathway

Herbs And Phytochemicals: Atherosclerosis, a chronic cardiovascular disease, is a leading cause of mortality among the elderly. This insidious condition is characterized by the deposition of lipoproteins, inflammatory responses, plaque formation, and calcification in the arterial walls. Inflammation is a central component in the initiation and progression of atherosclerosis. Atherosclerosis is often considered a chronic inflammatory disease. This inflammation contributes significantly to the physiological and pathological changes that occur during the development of atherosclerosis. Macrophages, key immune cells, play a pivotal role in regulating the inflammatory response. They can differentiate into two distinct subpopulations: proinflammatory macrophages (M1) and immunomodulatory alternatively activated macrophages (M2). An imbalance between these macrophage polarizations can lead to inflammatory conditions that exacerbate atherosclerotic plaque instability.


 
Notably, M1 macrophages release proinflammatory cytokines such as IL-6, IL-1β, IL-18, and TNF-α upon lipid uptake, leading to heightened inflammation. This inflammatory reaction, in turn, worsens atherosclerotic plaque instability. Therefore, targeting macrophage inflammation has emerged as a crucial potential strategy for antiatherosclerosis therapy. Toll-like receptor 4 (TLR4) is a key signaling pathway involved in macrophage inflammatory cascades in atherosclerosis.
 
Activation of TLR4 initiates intracellular signaling pathways through mitogen-activated protein kinases (MAPKs) and the transcription factor nuclear factor kappa B (NF-κB). These pathways regulate the gene expression of pro-inflammatory cytokines and other inflammatory mediators. It has been suggested that the absence of TLR4 or MyD88, an adaptor protein in the TLR4 pathway, can reduce atherosclerotic plaque formation in mice.
 
Furthermore, previous studies have shown that specific compounds extracted from plants, such as Val-Glu-Gly-Tyr peptide from Genus Ulva and flavonoids from Sophora tonkinensis, can inhibit inflammation by modulating the TLR4-NFκB/MAPK signaling pathway. Therefore, inhibiting the activation of the TLR4-NFκB/MAPK signaling pathway and alleviating the inflammatory response driven by macrophage polarization present promising avenues for anti-atherosclerosis research.
 
The Phytochemical Corilagin
Corilagin, a polyphenolic tannic acid compound found in plants of the Hypophyllum genus, has gained attention due to its various pharmacological properties. Clinical and basic theoretical research has revealed that corilagin exhibits antibacterial, antioxidant, anti-tumor, liver-protective, and anti-inflammatory activities. Modern pharmacological studies have shown that corilagin can inhibit atherosclerosis development in piglets or rabbits by regulating the expression of matrix metalloproteinases (MMP)-1, -2, and -9 or by inhibiting the proliferation of vascular smooth muscle cells (VSMCs) induced by oxidized low-density lipoprotein (ox-LDL). Additionally, researchers have found that corilagin can reduce the release of pro-inflammatory cytokines by inhibiting the TLR4 signaling pathway in monocytes/macrophages in vitro. Since macrophage polarization is closely associated with the TLR4 signaling pathway, corilagin's precise mechanism in regulating macrophage polarization remains unclear.< br />  
Molecular docking, a computational tool, is widely employed to predict the binding capacity and binding mode of receptor-drug molecular complexes. It has been used extensively to screen potential lead compounds for new chemical entities. In this study, researchers used molecular docking to investigate the binding interactions between corilagin and several key nodes involved in macrophage inflammation, including TLR4, MyD88, NF-κB p65, MAPK p38, and MAPK JNK. The crystal structures of these proteins have been reported, making them effective targets for studying macrophage inflammation.
 
Methods and Results
In this Herbs And Phytochemicals study by scientists from Yunnan University of Chinese Medicine-China and Binzhou Medical University-China, a combination of in vivo and in vitro studies, as well as molecular docking strategies, was employed to evaluate the effects and mechanisms of corilagin on atherosclerosis and macrophage polarization.
 
In vivo, ApoE−/− mice were fed a high-fat diet to establish an atherosclerotic model. The results showed that corilagin treatment had a significant inhibitory effect on plaque area and lipid accumulation in the aortic sinus of atherosclerotic mice. Macrophage polarization plays a crucial role in inflammation and atherosclerosis. Inflammatory reactions, driven by proinflammatory cytokines like TNF-α, IL-1β, IL-6, and IL-18, are known to promote atherosclerosis by inducing foam cell formation.
 
In this study, corilagin was found to significantly inhibit the production of these proinflammatory cytokines in high-fat diet-fed ApoE−/− mice and LPS-induced RAW264.6 cells. Moreover, corilagin decreased the expression of inducible nitric oxide synthase (iNOS) and promoted the expression of CD206 in aortic plaques. iNOS is a marker of the M1 macrophage phenotype, which has proinflammatory effects, while CD206 is associated with the M2 phenotype, which has anti-inflammatory effects. The results demonstrated that corilagin shifted macrophages from the M1-like phenotype to the M2-like phenotype, effectively suppressing the inflammatory response.
 
In the in vitro portion of the study, LPS-stimulated macrophages were used to investigate the activation and induction of M1-like polarization. After LPS stimulation, the M1 markers and pro-inflammatory factors significantly increased. This outcome suggested that corilagin could regulate macrophage polarization, though further research using Flow cytometry (FCM) is necessary to explore the specific effects on macrophage phenotype.
 
The phenotypic changes and functions of macrophages are regulated by various signaling pathways. Transcription factors, including TLR4-NF-κB and TLR4-MAPK, are known to be involved in M1 programming. The TLR4-NF-κB pathway is a classic pro-inflammatory signaling pathway. When stimulated by substances like LPS, the p65/p50 heterodimer (IκBα) becomes phosphorylated and is subsequently degraded by activation of IKKs. This process leads to the nuclear translocation of p65/p50 heterodimer, which activates the transcription of NF-κB target genes. In this study, the researchers demonstrated that corilagin suppressed the activation of NF-κB induced by LPS, reduced the phosphorylation of IκBα, and diminished the nuclear translocation of NF-κB p65 and its phosphorylation.
 
The TLR4-MAPK pathway is also critical in inflammation, with JNK and p38 known to be key players in IκBα degradation. Corilagin significantly inhibited the phosphorylation levels of JNK and p38, indicating its role in regulating the TLR4-MAPK pathway. These results suggest that TLR4-NF-κB and TLR4-MAPK/JNK/p38 pathways are involved in corilagin's ability to inhibit M1 polarization.
 
The molecular docking experiments further supported these findings. Corilagin demonstrated stable binding to several key nodes involved in macrophage inflammation, including TLR4, MyD88, NF-κB p65, MAPK P38, and MAPK JNK. The interaction energy between corilagin and MAPK P38 was particularly high, suggesting a strong affinity. This implies that corilagin may act on the TLR4-NF-κB/MAPK pathway with a multi-target effect, aligning with the experimental results from cell studies.
 
Future Directions
While this study provided critical insights into the anti-inflammatory properties of corilagin in the context of atherosclerosis, there is still much to be explored. For example, the specific target proteins of corilagin need to be further investigated. This could be accomplished through methods such as Surface Plasmon Resonance (SPR) or by conducting experiments in knockout models where target genes are inactivated. Further research is necessary to provide a solid basis for clinical application and resource development and utilization.
 
Conclusion
In summary, this research identifies corilagin as a promising compound for the treatment of atherosclerosis. Notably, it sheds light on a novel mechanism through which corilagin regulates macrophage polarization to suppress inflammation and prevent atherosclerosis. The findings suggest that corilagin's anti-inflammatory properties may be attributed to its ability to modulate the TLR4-NF-κB/MAPK pathway, making it a potential lead compound for the development of atherosclerosis treatment drugs. With further research and development, corilagin could become a cornerstone in the fight against atherosclerosis, offering hope for those at risk of this debilitating disease.
 
The study findings were published in the peer reviewed journal: Heliyon.
https://www.cell.com/heliyon/fulltext/S2405-8440(23)04167-1
 
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