Molecular mechanism underlying the TLR4 antagonistic and antiseptic activities of papiliocin, an insect innate immune response molecule

Abstract

Significance Similar to mammalian TLR4/MD-2, the Toll9/MD-2–like protein complex in the silkworm, Bombyx mori, acts as an innate pattern-recognition receptor that recognizes lipopolysaccharide (LPS) and induces LPS-stimulated expression of antimicrobial peptides such as cecropins. Here, we report that papiliocin, a cecropin-like insect antimicrobial peptide from the swallowtail butterfly, competitively inhibits the LPS-TLR4/MD-2 interaction by directly binding to human TLR4/MD-2. Structural elements in papiliocin, which are important in inhibiting TLR4 signaling via direct binding, are highly conserved among insect cecropins, indicating that its TLR4-antagonistic activity may be related to insect Toll9-mediated immune response against microbial infection. This study highlights the potential of papiliocin as a potent TLR4 antagonist and safe peptide antibiotic for treating gram-negative sepsis.

Rhamnetin, a Natural Flavonoid, Ameliorates Organ Damage in a Mouse Model of Carbapenem-Resistant Acinetobacter baumannii-Induced Sepsis

“…The host activates the innate and adaptive immune systems by mediating pro-inflammatory cytokines [ 34 ]. However, as the over-activation of pro-inflammatory cytokines leads to multi-organ failure, the initial anti-inflammatory function of macrophages plays a critical role in countering infections [ 35 ]. Hence, we measured the anti-inflammatory activity of rhamnetin after infecting murine macrophages with bacteria that continuously release various pathogen-associated molecular patterns, including LPS.…”

Antimicrobial peptides could antagonize uncontrolled inflammation via Toll-like 4 receptor

“…These molecules are widely studied not only for their physiological role in insect immunity, but also for their immunomodulatory characteristics (Hoffmann, 1995;Silvestro et al, 2000;Wu et al, 2018). Krishnan et al, (Krishnan et al, 2022), reported a new molecular mechanism with papiliocin antagonistic effect mediated by its direct binding to the TLR4/MD-2 complex. Such antagonistic effect occurs once peptide competes with LPS for TLR4/MD-2 complex binding site.…”

“…Krishnan et al, ( Krishnan et al, 2022 ), reported a new molecular mechanism with papiliocin antagonistic effect mediated by its direct binding to the TLR4/MD-2 complex. Such antagonistic effect occurs once peptide competes with LPS for TLR4/MD-2 complex binding site.…”

“…TLR4 inhibitors can prevent or decrease the exacerbated inflammatory process, contributing to reestablishing tissue homeostasis ( Li and Wu, 2021 ). TLR4 is well characterized in terms of its participation in inflammatory events, and has proved to be a very attractive target for therapies that are antagonistic to the uncontrolled inflammatory process ( Slivka et al, 2009 ; Krishnan et al, 2022 ).…”

“…The liquid cationic characteristic of AMPs attributes an electrostatic attraction to LPS present in the cell wall of Gram-negative bacteria ( Sun and Shang, 2015 ). The adhesion of antimicrobial peptides’ cationic surface to anionic membrane lipids may disrupt membranes and alter cell permeability ( Sun and Shang, 2015 ; Zhang et al, 2021 ; Krishnan et al, 2022 ). Furthermore, when AMPs interact with LPSs, they hamper TLR4/LPS binding, blocking the inflammatory pathway activation ( Sun and Shang, 2015 ; Krishnan et al, 2022 ).…”