Abstract
Oleanolic acid is a widely distributed natural product, which possesses promising antitumor, antiviral, antihyperlipidemic, and anti-inflammatory activities. A heterodimeric complex formed by integrin αM (CD11b) and integrin β2 (CD18) is highly expressed on monocytes and macrophages. In the current study, we demonstrate that the I domain of αM (αM-I domain) might present a potential cellular target for oleanolic acid. In vitro data show that oleanolic acid induces clustering of αM on macrophages and reduces their non-directional migration. In accordance with experimental data, molecular docking revealed that oleanolic acid binds to the αM-I domain in its extended-open form, the dominant conformation found in αM clusters. Molecular dynamics simulation revealed that oleanolic acid can increase the flexibility of the α7 helix and promote its movement away from the N-terminus, indicating that oleanolic acid may facilitate the conversion of the αM-I domain from the extended-closed to the extended-open conformation. As demonstrated by metadynamics simulation, oleanolic acid can destabilize the local minimum of the αM-I domain in the open conformation partially through disturbance of the interactions between α1 and α7 helices. In summary, we demonstrate that oleanolic acid might function as an allosteric agonist inducing clustering of αM on macrophages by shifting the balance from the closed to the extended-open conformation. The molecular target identified in this study might hold potential for a purposeful use of oleanolic acid to modulate chronic inflammatory responses.
Highlights
Oleanolic acid is one of the most abundant terpenoids isolated from different edible plants as well as from many medicinal plants including Panax ginseng and Eleutherococcus senticosus (Liu, 1995; Jin et al, 2020)
We have observed that Eleutherococcus senticosus bark extract enriched in oleanolic acid decreases the migratory activity of macrophages (Jin et al, 2020), which may point to increased cell adhesion as has previously been shown for the αMβ2 agonists, leukadherins (Maiguel et al, 2011)
The data of our study provide evidence that oleanolic acid may function as an allosteric agonist of integrin αM through binding to its αM-I domain
Summary
Oleanolic acid is one of the most abundant terpenoids isolated from different edible plants as well as from many medicinal plants including Panax ginseng and Eleutherococcus senticosus (Liu, 1995; Jin et al, 2020). Antiviral, anti-inflammatory, antidiabetic, and hepatoprotective activities in various animal models (Liu, 1995; Ayeleso et al, 2017). Oleanolic acid directly affects macrophages, their polarization and various functions. Oleanolic acid inhibited the IL-10-induced macrophage polarization to the M2c subtype (Fujiwara et al, 2011) and induced macrophage-like differentiation of myeloid cell lines (Liu, 1995). It has been shown that oleanolic acid reduces reactive oxygen species levels (ROS), though, it does not scavenge ROS directly, but functions as an indirect ROS regulator by increasing the generation of antioxidant glutathione and the expression of key antioxidant enzymes (Ayeleso et al, 2017). The molecular mechanisms, especially the upstream targets of oleanolic acid are still largely obscure
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call