Magic Peptide: Unique Properties of the LRR11 Peptide in the Activation of Leukotriene Synthesis in Human Neutrophils

Abstract

Neutrophil-mediated innate host defense mechanisms include pathogen elimination through bacterial phagocytosis, which activates the 5-lipoxygenase (5-LOX) product synthesis. Here, we studied the effect of synthetic oligodeoxyribonucleotides (ODNs), which mimic the receptor-recognized sites of bacterial (CpG-ODNs) and genomic (G-rich ODNs) DNAs released from the inflammatory area, on the neutrophil functions after cell stimulation with Salmonella typhimurium. A possible mechanism for ODN recognition by Toll-like receptor 9 (TLR9) and RAGE receptor has been proposed. We found for the first time that the combination of the magic peptide LRR11 from the leucine-rich repeat (LRR) of TLR9 with the CpG-ODNs modulates the uptake and signaling from ODNs, in particular, dramatically stimulates 5-LOX pathway. Using thickness shear mode acoustic method, we confirmed the specific binding of CpG-ODNs, but not G-rich ODN, to LRR11. The RAGE receptor has been shown to play an important role in promoting ODN uptake. Thus, FPS-ZM1, a high-affinity RAGE inhibitor, suppresses the synthesis of 5-LOX products and reduces the uptake of ODNs by neutrophils; the inhibitor effect being abolished by the addition of LRR11. The results obtained revealed that the studied peptide-ODN complexes possess high biological activity and can be promising for the development of effective vaccine adjuvants and antimicrobial therapeutics.

Metastatic Prostate Cancer Cells Secrete Methylglyoxal-Derived MG-H1 to Reprogram Human Osteoblasts into a Dedifferentiated, Malignant-like Phenotype: A Possible Novel Player in Prostate Cancer Bone Metastases

“…These results suggested that MG-derived MG-H1 released by bone metastasis-derived PC3 cells reprograms human OB into a mesenchymal-, malignant-like phenotype through a RAGE-dependent mechanism. Importantly, upon MG-H1-containing PC3 CM exposure, blockade of RAGE with the high-affinity RAGE-specific inhibitor FPS-ZM1 [ 41 , 42 ], rescued OB dedifferentiation and re-wiring, evaluated by VIM, CADH11, Runx 2, CD44, migration, and PSMA levels ( Figure 11 d).…”

“…These results suggested that MG-derived MG-H1 released by bone metastasis-derived PC3 cells reprograms human OB into a mesenchymal-, malignant-like phenotype through a RAGE-dependent mechanism. Importantly, upon MG-H1-containing PC3 CM exposure, blockade of RAGE with the high-affinity RAGE-specific inhibitor FPS-ZM1 [41,42], rescued OB dedifferentiation and re-wiring, evaluated by VIM, CADH11, Runx 2, CD44, migration, and PSMA levels (Figure 11d). Overall, these findings indicated that MG-derived MG-H1 released by bone metastasis-derived PC3 cells reprogrammed human primary OB into a mesenchymal-, malignantlike phenotype through a RAGE-dependent mechanism with the involvement of ROS and NF-kB signaling.…”